@article{li_wang_archibong_wu_chen_hu_ci_chen_wang_wen_et al._2022, title={Scattered seeding of CAR T cells in solid tumors augments anticancer efficacy}, volume={9}, ISSN={["2053-714X"]}, DOI={10.1093/nsr/nwab172}, abstractNote={Chimeric antigen receptor T cell (CAR T) therapy was a milestone in the treatment of relapsed and refractory B cell malignancies. However, beneficial effects of CAR T cells have not been obtained in solid tumors yet. Herein, we implement a porous microneedle patch that accommodates CAR T cells and allows in situ penetration-mediated seeding of CAR T cells when implanted in the tumor bed or in the post-surgical resection cavity. CAR T cells loaded in the pores of the microneedle tips were readily escorted to the tumor in an evenly scattered manner without losing their activity. Such microneedle-mediated local delivery enhanced infiltration and immunostimulation of CAR T cells as compared to direct intratumoral injection. This tailorable patch offers a transformative platform for scattered seeding of living cells for treating a variety of tumors.}, number={3}, journal={NATIONAL SCIENCE REVIEW}, author={Li, Hongjun and Wang, Zejun and Archibong, Edikan and Wu, Qing and Chen, Guojun and Hu, Quanyin and Ci, Tianyuan and Chen, Zhaowei and Wang, Jinqiang and Wen, Di and et al.}, year={2022}, month={Mar} }
 @article{chen_li_bian_wang_chen_zhang_miao_wen_wang_wan_et al._2021, title={Bioorthogonal catalytic patch}, ISSN={["1748-3395"]}, DOI={10.1038/s41565-021-00910-7}, abstractNote={Bioorthogonal catalysis mediated by transition metals has inspired a new subfield of artificial chemistry complementary to enzymatic reactions, enabling the selective labelling of biomolecules or in situ synthesis of bioactive agents via non-natural processes. However, the effective deployment of bioorthogonal catalysis in vivo remains challenging, mired by the safety concerns of metal toxicity or complicated procedures to administer catalysts. Here, we describe a bioorthogonal catalytic device comprising a microneedle array patch integrated with Pd nanoparticles deposited on TiO2 nanosheets. This device is robust and removable, and can mediate the local conversion of caged substrates into their active states in high-level living systems. In particular, we show that such a patch can promote the activation of a prodrug at subcutaneous tumour sites, restoring its parent drug's therapeutic anticancer properties. This in situ applied device potentiates local treatment efficacy and eliminates off-target prodrug activation and dose-dependent side effects in healthy organs or distant tissues.}, journal={NATURE NANOTECHNOLOGY}, author={Chen, Zhaowei and Li, Hongjun and Bian, Yijie and Wang, Zejun and Chen, Guojun and Zhang, Xudong and Miao, Yimin and Wen, Di and Wang, Jinqiang and Wan, Gang and et al.}, year={2021}, month={May} }
 @article{sun_wang_hu_zhou_khademhosseini_gu_2020, title={CRISPR-Cas12a delivery by DNA-mediated bioresponsive editing for cholesterol regulation}, volume={6}, ISSN={["2375-2548"]}, DOI={10.1126/sciadv.aba2983}, abstractNote={CRISPR-Cas12a represents an efficient tool for genome editing in addition to the extensively investigated CRISPR-Cas9. However, development of efficient nonviral delivery system for CRISPR-Cas12a remains challenging. Here, we demonstrate a DNA nanoclew (NC)-based carrier for delivery of Cas12a/CRISPR RNA (crRNA) ribonucleoprotein (RNP) toward regulating serum cholesterol levels. The DNA NC could efficiently load the Cas12a/crRNA RNP through complementation between the DNA NC and the crRNA. Addition of a cationic polymer layer condensed the DNA-templated core and allowed further coating of a charge reversal polymer layer, which makes the assembly negatively charged under a physiological pH but reverts to positive charge under an acidic environment. When Pcsk9 was selected as the target gene because of its important role in regulating the level of serum cholesterol, efficient Pcsk9 disruption was observed in vivo (~48%), significantly reducing the expression of PCSK9 and gaining the therapeutic benefit of cholesterol control (~45% of cholesterol reduction).}, number={21}, journal={SCIENCE ADVANCES}, author={Sun, Wujin and Wang, Jinqiang and Hu, Quanyin and Zhou, Xingwu and Khademhosseini, Ali and Gu, Zhen}, year={2020}, month={May} }
 @article{zhang_kang_wang_yan_chen_cheng_huang_gu_2020, title={Engineered PD-L1-Expressing Platelets Reverse New-Onset Type 1 Diabetes}, volume={32}, ISSN={["1521-4095"]}, DOI={10.1002/adma.201907692}, abstractNote={The pathogenesis of Type 1 diabetes (T1D) arises from the destruction of insulin-producing β-cells by islet-specific autoreactive T cells. Inhibition of islet-specific autoreactive T cells to rescue β-cells is a promising approach to treat new-onset T1D. The immune checkpoint signal axis programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) can effectively regulate the activity of T cells and prevent autoimmune attack. Here, megakaryocyte progenitor cells are genetically engineered to overexpress PD-L1 to produce immunosuppressive platelets. The PD-L1-overexpressing platelets (designated PD-L1 platelets) accumulate in the inflamed pancreas and may suppress the activity of pancreas autoreactive T cells in newly hyperglycemic non-obese diabetic (NOD) mice, protecting the insulin-producing β-cells from destruction. Moreover, PD-L1 platelet treatment also increases the percentage of the regulatory T cells (Tregs) and maintains immune tolerance in the pancreas. It is demonstrated that the rescue of β-cells by PD-L1 platelets can effectively maintain normoglycemia and reverse diabetes in newly hyperglycemic NOD mice.}, number={26}, journal={ADVANCED MATERIALS}, author={Zhang, Xudong and Kang, Yang and Wang, Jinqiang and Yan, Junjie and Chen, Qian and Cheng, Hao and Huang, Peng and Gu, Zhen}, year={2020}, month={Jul} }
 @article{yu_wang_zhang_chen_mao_ye_kahkoska_buse_langer_gu_2020, title={Glucose-responsive insulin patch for the regulation of blood glucose in mice and minipigs}, volume={4}, ISSN={["2157-846X"]}, DOI={10.1038/s41551-019-0508-y}, abstractNote={Glucose-responsive insulin delivery systems that mimic pancreatic endocrine function could enhance health and improve quality of life for people with type 1 and type 2 diabetes with reduced β-cell function. However, insulin delivery systems with rapid in vivo glucose-responsive behaviour typically have limited insulin-loading capacities and cannot be manufactured easily. Here, we show that a single removable transdermal patch, bearing microneedles loaded with insulin and a non-degradable glucose-responsive polymeric matrix, and fabricated via in situ photopolymerization, regulated blood glucose in insulin-deficient diabetic mice and minipigs (for minipigs >25 kg, glucose regulation lasted >20 h with patches of ~5 cm2). Under hyperglycaemic conditions, phenylboronic acid units within the polymeric matrix reversibly form glucose–boronate complexes that—owing to their increased negative charge—induce the swelling of the polymeric matrix and weaken the electrostatic interactions between the negatively charged insulin and polymers, promoting the rapid release of insulin. This proof-of-concept demonstration may aid the development of other translational stimuli-responsive microneedle patches for drug delivery. A single removable transdermal patch bearing microneedles loaded with insulin and a non-degradable glucose-responsive polymeric matrix regulates blood glucose in insulin-deficient diabetic mice and minipigs.}, number={5}, journal={NATURE BIOMEDICAL ENGINEERING}, author={Yu, Jicheng and Wang, Jinqiang and Zhang, Yuqi and Chen, Guojun and Mao, Weiwei and Ye, Yanqi and Kahkoska, Anna R. and Buse, John B. and Langer, Robert and Gu, Zhen}, year={2020}, month={May}, pages={499–506} }
 @article{ruan_hu_wen_chen_chen_lu_wang_cheng_lu_gu_2019, title={A Dual-Bioresponsive Drug-Delivery Depot for Combination of Epigenetic Modulation and Immune Checkpoint Blockade}, volume={31}, ISSN={["1521-4095"]}, DOI={10.1002/adma.201806957}, abstractNote={Patients with advanced melanoma that is of low tumor-associated antigen (TAA) expression often respond poorly to PD-1/PD-L1 blockade therapy. Epigenetic modulators, such as hypomethylation agents (HMAs), can enhance the antitumor immune response by inducing TAA expression. Here, a dual bioresponsive gel depot that can respond to the acidic pH and reactive oxygen species (ROS) within the tumor microenvironment (TME) for codelivery of anti-PD1 antibody (aPD1) and Zebularine (Zeb), an HMA, is engineered. aPD1 is first loaded into pH-sensitive calcium carbonate nanoparticles (CaCO3 NPs), which are then encapsulated in the ROS-responsive hydrogel together with Zeb (Zeb-aPD1-NPs-Gel). It is demonstrated that this combination therapy increases the immunogenicity of cancer cells, and also plays roles in reversing immunosuppressive TME, which contributes to inhibiting the tumor growth and prolonging the survival time of B16F10-melanoma-bearing mice.}, number={17}, journal={ADVANCED MATERIALS}, author={Ruan, Huitong and Hu, Quanyin and Wen, Di and Chen, Qian and Chen, Guojun and Lu, Yifei and Wang, Jinqiang and Cheng, Hao and Lu, Weiyue and Gu, Zhen}, year={2019}, month={Apr} }
 @article{yang_chen_wen_chen_wang_chen_wang_zhang_zhang_hu_et al._2019, title={A Therapeutic Microneedle Patch Made from Hair-Derived Keratin for Promoting Hair Regrowth}, volume={13}, ISSN={["1936-086X"]}, DOI={10.1021/acsnano.8b09573}, abstractNote={Activating hair follicle stem cells (HFSCs) to promote hair follicle regrowth holds promise for hair loss therapy, while challenges still remain to develop a scenario that enables enhanced therapeutic efficiency and easy administration. Here we describe a detachable microneedle patch-mediated drug delivery system, mainly made from hair-derived keratin, for sustained delivery of HFSC activators. It was demonstrated that this microneedle device integrated with mesenchymal stem cell (MSC)-derived exosomes and a small molecular drug, UK5099, could enhance the treatment efficiency at a reduced dosage, leading to promoted pigmentation and hair regrowth within 6 days through two rounds of administration in a mouse model. This microneedle-based transdermal drug delivery approach shows augmented efficacy compared to the subcutaneous injection of exosomes and topical administration of UK5099.}, number={4}, journal={ACS NANO}, author={Yang, Guang and Chen, Qian and Wen, Di and Chen, Zhaowei and Wang, Jinqiang and Chen, Guojun and Wang, Zejun and Zhang, Xudong and Zhang, Yuqi and Hu, Quanyin and et al.}, year={2019}, month={Apr}, pages={4354–4360} }
 @article{wang_wang_yu_zhang_zeng_gu_2019, title={A forskolin-conjugated insulin analog targeting endogenous glucose-transporter for glucose-responsive insulin delivery}, volume={7}, ISSN={["2047-4849"]}, DOI={10.1039/c9bm01283d}, abstractNote={A new insulin analog has been obtained by modifying insulin with forskolin (designated as insulin-F), a glucose transporter (Glut) inhibitor. Insulin-F is capable of binding to Glut on the plasma membrane in a glucose-dependent manner.}, number={11}, journal={BIOMATERIALS SCIENCE}, author={Wang, Jinqiang and Wang, Zejun and Yu, Jicheng and Zhang, Yuqi and Zeng, Yi and Gu, Zhen}, year={2019}, month={Nov}, pages={4508–4513} }
 @article{wen_wang_van den driessche_chen_zhang_chen_li_soto_liu_ohashi_et al._2019, title={Adipocytes as Anticancer Drug Delivery Depot}, volume={1}, ISSN={["2590-2385"]}, DOI={10.1016/j.matt.2019.08.007}, abstractNote={•Engineered adipocyte serves as a Trojan horse for anticancer drug delivery•Tumor lipid metabolism can be leveraged for drug discovery and drug delivery•Intratumoral or postsurgical therapy can be achieved based on this cellular depot The tumor microenvironment composed of nonmalignant cells often promotes tumor growth by providing growth factors and preventing the infiltration of tumor-killing immune cells. It could be valuable to leverage the therapeutic potential of the nonmalignant cells within the tumor microenvironment for anticancer treatment. In this work, the adipocytes have been engineered with the encapsulation of an anticancer fatty acid and a bioresponsive doxorubicin prodrug for chemotherapy and simultaneously inducing an immunogenic tumor phenotype. These Trojan horse-like injectable engineered adipocytes can serve as a drug-delivery depot for sustained drug release with suppressed primary tumor growth and postsurgical tumor recurrence. This adipocyte-mediated drug-delivery strategy expands the scope of cell therapy and could be extended for treating other diseases associated with lipid metabolism pathways. Tumor-associated adipocytes promote tumor growth by providing energy and causing chronic inflammation. Here, we have exploited the lipid metabolism to engineer adipocytes that serve as a depot to deliver cancer therapeutics at the tumor site. Rumenic acid (RA), as an anticancer fatty acid, and a doxorubicin prodrug (pDox) with a reactive oxygen species (ROS)-cleavable linker, are encapsulated in adipocytes to deliver therapeutics in a tumor-specific bioresponsive manner. After intratumoral or postsurgical administration, lipolysis releases the RA and pDox that is activated by intracellular ROS-responsive conversion, subsequently promoting antitumor efficacy. Furthermore, downregulation of PD-L1 expression is observed in tumor cells, favoring the emergence of CD4+ and CD8+ T cell-mediated immune responses. Tumor-associated adipocytes promote tumor growth by providing energy and causing chronic inflammation. Here, we have exploited the lipid metabolism to engineer adipocytes that serve as a depot to deliver cancer therapeutics at the tumor site. Rumenic acid (RA), as an anticancer fatty acid, and a doxorubicin prodrug (pDox) with a reactive oxygen species (ROS)-cleavable linker, are encapsulated in adipocytes to deliver therapeutics in a tumor-specific bioresponsive manner. After intratumoral or postsurgical administration, lipolysis releases the RA and pDox that is activated by intracellular ROS-responsive conversion, subsequently promoting antitumor efficacy. Furthermore, downregulation of PD-L1 expression is observed in tumor cells, favoring the emergence of CD4+ and CD8+ T cell-mediated immune responses. Cancer cells are frequently surrounded by nonmalignant cells that support tumor development.1Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (42748) Google Scholar Tumor-associated adipocytes (TAAs) are present within the tumor microenvironment (TME) and are recognized to promote angiogenesis by secreting adipokines that include hormones, growth factors, and cytokines.2Santander A.M. Lopez-Ocejo O. Casas O. Agostini T. Sanchez L. Lamas-Basulto E. Carrio R. Cleary M.P. Gonzalez-Perez R.R. Torroella-Kouri M. Paracrine interactions between adipocytes and tumor cells recruit and modify macrophages to the mammary tumor microenvironment: the role of obesity and inflammation in breast adipose tissue.Cancers (Basel). 2015; 7: 143-178Crossref PubMed Scopus (69) Google Scholar Adipokines contribute in recruiting immune cells that favor the generation of low-grade chronic inflammation3Correa L.H. Correa R. Farinasso C.M. de Sant'Ana Dourado L.P. Magalhaes K.G. Adipocytes and macrophages interplay in the orchestration of tumor microenvironment: new implications in cancer progression.Front. Immunol. 2017; 8: 1129Crossref PubMed Scopus (49) Google Scholar and abundance of reactive oxygen species (ROS) in the TME and tumor cells.4Nieman K.M. Romero I.L. Van Houten B. Lengyel E. Adipose tissue and adipocytes support tumorigenesis and metastasis.Biochim. Biophys. Acta. 2013; 1831: 1533-1541Crossref PubMed Scopus (499) Google Scholar, 5Liou G.Y. Storz P. Reactive oxygen species in cancer.Free Radic. Res. 2010; 44: 479-496Crossref PubMed Scopus (2034) Google Scholar Growth factors, including vascular endothelial growth factor (VEGF), promote angiogenesis and tumor growth.6Cao Y. Angiogenesis and vascular functions in modulation of obesity, adipose metabolism, and insulin sensitivity.Cell Metab. 2013; 18: 478-489Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar In the TME, fatty acids in lipid droplets from the adipocytes can also provide energy to cancer cells7Zhang M. Di Martino J.S. Bowman R.L. Campbell N.R. Baksh S.C. Simon-Vermot T. Kim I.S. Haldeman P. Mondal C. Yong-Gonzales V. et al.Adipocyte-derived lipids mediate melanoma progression via FATP proteins.Cancer Discov. 2018; 8: 1006-1025Crossref PubMed Scopus (171) Google Scholar, 8Miranda F. Mannion D. Liu S. Zheng Y. Mangala L.S. Redondo C. Herrero-Gonzalez S. Xu R. Taylor C. Chedom D.F. et al.Salt-inducible kinase 2 couples ovarian cancer cell metabolism with survival at the adipocyte-rich metastatic niche.Cancer Cell. 2016; 30: 273-289Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar through the fatty acid-binding protein 4 (FABP4) and tumor cell-induced lipolysis.9Nieman K.M. Kenny H.A. Penicka C.V. Ladanyi A. Buell-Gutbrod R. Zillhardt M.R. Romero I.L. Carey M.S. Mills G.B. Hotamisligil G.S. et al.Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth.Nat. Med. 2011; 17: 1498-1503Crossref PubMed Scopus (1427) Google Scholar Moreover, recent studies indicate that interleukin-6 (IL-6) and leptin secreted by the adipocyte induce PD-L1 expression in cancer cells via activation of the JAK/Stat3 pathway.10Xu L. Shen M. Chen X. Zhu R. Yang D.R. Tsai Y. Keng P.C. Chen Y. Lee S.O. Adipocytes affect castration-resistant prostate cancer cells to develop the resistance to cytotoxic action of NK cells with alterations of PD-L1/NKG2D ligand levels in tumor cells.Prostate. 2018; 78: 353-364Crossref PubMed Scopus (33) Google Scholar A switch from white fat to brown fat caused by tumor cells11Petruzzelli M. Schweiger M. Schreiber R. Campos-Olivas R. Tsoli M. Allen J. Swarbrick M. Rose-John S. Rincon M. Robertson G. et al.A switch from white to brown fat increases energy expenditure in cancer-associated cachexia.Cell Metab. 2014; 20: 433-447Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar can also promote the direct expression of PD-L1 in adipocytes.12Ingram J.R. Dougan M. Rashidian M. Knoll M. Keliher E.J. Garrett S. Garforth S. Blomberg O.S. Espinosa C. Bhan A. et al.PD-L1 is an activation-independent marker of brown adipocytes.Nat. Commun. 2017; 8: 647Crossref PubMed Scopus (74) Google Scholar Therefore, targeting TAAs may be used to interrupt and eliminate a significant source of nutrients and immune protection for tumor cells. Here, we have leveraged adipocytes as a drug delivery depot to achieve local and sustained release of chemotherapeutics within the TME (Figure 1A). A ROS-responsive doxorubicin prodrug (pDox) is synthesized (Figure 1B) and encapsulated into adipocytes together with rumenic acid (RA), an anticancer fatty acid,13Tanmahasamut P. Liu J. Hendry L.B. Sidell N. Conjugated linoleic acid blocks estrogen signaling in human breast cancer cells.J. Nutr. 2004; 134: 674-680Crossref PubMed Scopus (81) Google Scholar, 14Arab A. Akbarian S.A. Ghiyasvand R. Miraghajani M. The effects of conjugated linoleic acids on breast cancer: a systematic review.Adv. Biomed. Res. 2016; 5: 115Crossref PubMed Google Scholar, 15Lu G. Zhang G. Zheng X. Zeng Y. Xu Z. Zeng W. Wang K. C9, t11- conjugated linoleic acid induces HCC cell apoptosis and correlation with PPAR-gamma signaling pathway.Am. J. Transl. Res. 2015; 7: 2752-2763PubMed Google Scholar, 16Ochoa J.J. Farquharson A.J. Grant I. Moffat L.E. Heys S.D. Wahle K.W. Conjugated linoleic acids (CLAs) decrease prostate cancer cell proliferation: different molecular mechanisms for cis-9, trans-11 and trans-10, cis-12 isomers.Carcinogenesis. 2004; 25: 1185-1191Crossref PubMed Scopus (133) Google Scholar which meanwhile enhances the loading capacity of pDox inside the adipocytes. pDox can be delivered to cancer cells via activation of the lipid metabolic pathway mediated by FABP4 (Figure 1C) without affecting their physiologic lipid accumulation (Figure 1E). Finally, downregulation of PD-L1 in tumor cells mediated by engineered adipocytes promotes the effector function of infiltrating T cells (Figure 1D). We co-cultured 3T3-L1 cell-differentiated adipocytes with different cancer cells in a transwell system. Normal adipocytes promoted the growth of tumor cells (Figures S1A–S1D). Furthermore, adipokine profiling of the co-culture supernatant showed high levels of resistin and VEGF, known to facilitate tumor cell growth and metastasis,17Pang L. Zhang Y. Yu Y. Zhang S. Resistin promotes the expression of vascular endothelial growth factor in ovary carcinoma cells.Int. J. Mol. Sci. 2013; 14: 9751-9766Crossref PubMed Scopus (27) Google Scholar and lipocalin-2, known to drive brown fat activation in adipocytes18Zhang Y. Guo H. Deis J.A. Mashek M.G. Zhao M. Ariyakumar D. Armien A.G. Bernlohr D.A. Mashek D.G. Chen X. Lipocalin 2 regulates brown fat activation via a nonadrenergic activation mechanism.J. Biol. Chem. 2014; 289: 22063-22077Crossref PubMed Scopus (50) Google Scholar as well as lipolysis that provides energy to tumor cells (Figures S2 and S3). To reverse the protumorigenic role of TAAs, we first evaluated the in vitro toxicity of the anticancer RA (Figure S1E), also named 9Z,11E-conjugated linoleic acid, and encapsulated it into adipocytes, followed by co-culturing these engineered adipocytes with tumor cells in transwell assays. Adipocytes loaded with RA ([email protected]) significantly inhibited the growth of B16F10 and E0771 cells compared with nontreated cancer cells (Figures S1F and S1G). Furthermore, we observed that [email protected] inhibited the expression of PD-L1 in B16F10 cells (Figure S1H), and favorably modified the profile of adipokine secretion (Figures S2 and S3), suggesting that this strategy could be exploited to improve antitumor effects mediated by effector T cells. The mechanism studies indicated that the downregulated phosphorylation of the PD-L1 upstream regulators, including STAT3 and AKT,19Song T.L. Nairismagi M.L. Laurensia Y. Lim J.Q. Tan J. Li Z.M. Pang W.L. Kizhakeyil A. Wijaya G.C. Huang D.C. et al.Oncogenic activation of the STAT3 pathway drives PD-L1 expression in natural killer/T-cell lymphoma.Blood. 2018; 132: 1146-1158Crossref PubMed Scopus (159) Google Scholar, 20Lastwika K.J. Wilson 3rd, W. Li Q.K. Norris J. Xu H. Ghazarian S.R. Kitagawa H. Kawabata S. Taube J.M. Yao S. et al.Control of PD-L1 expression by oncogenic activation of the AKT-mTOR pathway in non-small cell lung cancer.Cancer Res. 2016; 76: 227-238Crossref PubMed Scopus (465) Google Scholar contributed to the PD-L1 downregulation by [email protected] (Figure S1I). The antitumor effects of [email protected] were evaluated by utilizing the B16F10 melanoma mouse model. TAAs were detected within the TME (Figure S4A), and intratumor injection of [email protected] significantly delayed tumor growth (Figures 1F–1I and S4B) without evident toxicity (Figure S4C). Moreover, 2 days after the second injection of [email protected], we observed lower PD-L1 expression in tumor cells (Figures 1J and S4D), increased tumor-infiltrating CD4+ and CD8+ T cells (Figures 1K, 1L, and S4E) and reduced regulatory T cells (Tregs) (Figures 1M and S4F) compared with control treatments. [email protected] tumor suppression was confirmed by the TUNEL assay (Figure 1N), while immunofluorescence staining of infiltrated CD4+ and CD8+ T cells further supported the transition to an immunogenic tumor phenotype (Figure 1O). The serum concentration of several cytokines was also determined, indicating significant downregulation of IL-6 and interferon-γ (Figure S4G), which might also contribute to the PD-L1 downregulation.21Garcia-Diaz A. Shin D.S. Moreno B.H. Saco J. Escuin-Ordinas H. Rodriguez G.A. Zaretsky J.M. Sun L. Hugo W. Wang X. et al.Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression.Cell Rep. 2017; 19: 1189-1201Abstract Full Text Full Text PDF PubMed Scopus (869) Google Scholar To further verify the immunomodulatory effect of [email protected] to the TME, we performed CD4- and CD8-depletion studies. The anticancer effect of [email protected] was significantly reversed after CD4 and CD8 depletion (Figure S5). We further investigated the antitumor activity of [email protected] in a tumor resection model. [email protected] encapsulated into a fibrin gel and injected into the tumor resection cavity significantly delayed tumor recurrence and growth (Figures S6A–S6D) without evident toxicity (Figure S6E). In this model, we also observed decreased expression of PD-L1 in tumor cells (Figures S6F and S6J), increased tumor-infiltrating CD4+ T cells (Figures S6G and S6K) and CD8+ T cells (Figures S6H and S6K), and decreased Tregs (Figures S6I and S6L). These results were further confirmed by immunohistochemistry and immunofluorescence staining, showing enhanced tumor cell apoptosis (Figure S6M) and T cell infiltration (Figure S6N). To further improve the therapeutic index of [email protected], we synthesized a Dox prodrug by conjugating Dox to the oleic acid with a phenylboronic acid-based ROS-responsive linker (Figures S7–S13), which can be cleaved in the presence of tumor-derived ROS.22Lu Y. Aimetti A.A. Langer R. Gu Z. Bioresponsive materials.Nat. Rev. Mater. 2016; 1: 16075Crossref Scopus (976) Google Scholar Upon oxidation in 10 mM H2O2, pDox was converted to Dox within 48 h (Figure S14A). We hypothesized that the lipid conjugation in pDox would enhance the uptake of pDox by cancer cells through the lipid metabolic pathway. Binding of pDox and FABP4 was simulated (Figure 2A) and quantitatively characterized by the fluorescence polarization (Figures 2B and 2C). pDox had a high binding affinity to FABP4 (KD = 23.1 nM), while there was almost no binding between Dox and FABP4. To simulate the binding interaction, we modified the structure of the linoleic acid and docked it into the FABP4 binding pocket (Figure S15A).23Friesner R.A. Banks J.L. Murphy R.B. Halgren T.A. Klicic J.J. Mainz D.T. Repasky M.P. Knoll E.H. Shelley M. Perry J.K. et al.Glide: a new approach for rapid, accurate docking and scoring. 1. method and assessment of docking accuracy.J. Med. Chem. 2004; 47: 1739-1749Crossref PubMed Scopus (6228) Google Scholar, 24Halgren T.A. Murphy R.B. Friesner R.A. Beard H.S. Frye L.L. Pollard W.T. Banks J.L. Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening.J. Med. Chem. 2004; 47: 1750-1759Crossref PubMed Scopus (3281) Google Scholar Furthermore, the ROS-responsive linker was constructed and conjugated to the lipid chain (Figure S15B). The pDox structure was generated using the Schrödinger Maestro's 3D-sketcher followed by an energy minimization procedure (Figure S15C) and a full-atom, 20-ns molecular dynamics simulation (Figure S16).25Guo Z. Mohanty U. Noehre J. Sawyer T.K. Sherman W. Krilov G. Probing the alpha-helical structural stability of stapled p53 peptides: molecular dynamics simulations and analysis.Chem. Biol. Drug Des. 2010; 75: 348-359Crossref PubMed Scopus (344) Google Scholar The binding affinity of lipids to FABP4 was significantly improved with the attached linker (Figures S15A and S15B). Dox attachment did not significantly alter the binding affinity of the ligand, with Dox staying outside of the binding site, and pDox was indeed predicted to be a strong binder to FABP4 (Figure S15C). We also analyzed the dynamics of lipid (Video S1), lipid plus linker (Video S2), and pDox (Video S3), verifying their interactions with the FABP4 binding pocket. eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiI1MWZiODQ5NDA4YTMwZGE5NzRkZDcxZjhlODBiZWE1MiIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc4NDg0Njg4fQ.DM1XS9QVmk8ndnGdWd1FuRsEgu5tfyRk6iYpIoqvxcjoiqcjhLM3W__LSXdr3YhGdlk3kGOq10o0ZO5d08TVUBNCMHmXo6DoAc3DI_56xOR3E7bdqzzALsXBnCoHcdrkpTWcWLkqPU-cjG9m_nD5GJdme28XIQzcQepx4a7iHXHZqXVe_WSJ2ik3uQuOWi_OPEZSNcGe8hOSE7M9MVVWsnToPjZoLsu_9NlyhL_zcYXoJLcPOebqIOYJuezI9kTsebWcZLBDhUyUPlqmoXrn-CpVhuP87NQRKmWLuFdQVY1dMxflsFD5HXhlD6pSBe41yAW-IroVtvzK8uzA3XkXOw Download .mp4 (27.79 MB) Help with .mp4 files Video S1. Simulation of the Binding between FABP4 and Stearic Acid eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiIyYjFkNmViZmZhNzVhNjRjMmRjODQxZGMzYTRhODk4NCIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc4NDg0Njg4fQ.DsGKIAhm32C5MdTQc8qHUVqIQaGn37TYd4nroYqq9gtdTfhgZADXiAlHOTt0eoilEueLv41kaoABijkcfgJGZfPeF1g2e92OPwSixR2hqSm5AMkLLcyg0NMkAbC3troeghkkc7KdH-r84d05AwQMynicm4jSKlDnx0uPRivJNO-tQfoHOEVpMKFYoMVuNOP-4D8EOcZzB5DufA7P_c5aprR-ZcktCiUobjkgdtJr5JL3Pg412ES7IbhSc887GsQpdIAJZEqN7C6XFZIFPURnfPRBGCK2_fpQkZE3hsX7KPOt0XXhMDvdc78kMcdifoLl6osfMu7pdY4fWNatybij8A Download .mp4 (26.01 MB) Help with .mp4 files Video S2. Simulation of the Binding between FABP4 and Stearic Acid plus the ROS-Responsive Linker eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiIwMDA2ZjNjMTJmMWU4OTNlZTI1NjdmMzJkZmI1ZDY2YiIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc4NDg0Njg4fQ.OLpLAVDu_sWui83nPYBPWkCYS2cfgr9dFTsloBeyW7mNNH0Do8c7tRNxrHDhjK8svzmPwOw3wCi67AuKvm9C6Ba7A10qwvHUryt11CnpgPAlofg12wVhOCQLTy14jnG3IFtFy7AW5Kv8W_FqINAL48FOv_PMCDnN2GM4yq706uA_vclge5wqJuB0T4iyK2zeCjAb-GgY80VfPGwxxrQBsvYIR5uulx5FCzhONpuT97Q7nAjN5ZcxfX7DoazLdcM-hDk4ZJ_NiObEr028PGgrekWmA_xM1_XuKN7AwTMVi24dEmpAAWjUnPSgEiuQgcfR-_W57BkWkaqmqqaArmJ3Vw Download .mp4 (27.77 MB) Help with .mp4 files Video S3. Simulation of the Binding between FABP4 and pDox Next, we assessed the cytotoxicity of pDox compared with Dox toward B16F10 (Figure 2D), A375 (Figure 2E), E0771 (Figure 2F), and MCF-7 (Figure 2G) cells. The IC50 of pDox toward B16F10, A375, and E0771 cells was about 1.5-fold higher than that of Dox. Dox and pDox were then added to 3T3-L1 cells to obtain [email protected] and [email protected], respectively, which were then co-cultured with B16F10 (Figure 2H) and E0771 (Figure 2I) cells in a transwell assay. [email protected] showed enhanced cytotoxicity compared with [email protected], and this effect was significantly reduced by BMS309403 that inhibits FABP4 (iFABP4) (Figure 2J). In accordance with a previous report,26Biondo L.A. Lima Junior E.A. Souza C.O. Cruz M.M. Cunha R.D. Alonso-Vale M.I. Oyama L.M. Nascimento C.M. Pimentel G.D. Dos Santos R.V. et al.Impact of doxorubicin treatment on the physiological functions of white adipose tissue.PLoS One. 2016; 11: e0151548Crossref PubMed Scopus (28) Google Scholar Dox inhibited lipid accumulation in adipocytes (Figures 2K, S17A, and S17B). In addition, pDox could be efficiently encapsulated into adipocytes (Figure 2L) and accumulated in the lipid droplets (Figure 2M). During pDox absorption, iFABP4 did not affect the uptake of pDox in adipocytes. However, it significantly inhibited the transportation of pDox from adipocytes to B16F10 cells in the transwell assay (Figure 2N). We further determined the antitumor effects of combining pDox and RA in B16F10 and E0771 cell lines (Figures 3A and 3B ; combination index for B16F10 was 0.57). Both pDox and Dox were effectively loaded into [email protected] (designated Dox + [email protected], pDox + [email protected]) (Figure 3C) following the diffusion process,27Thompson B.R. Lobo S. Bernlohr D.A. Fatty acid flux in adipocytes: the in's and out's of fat cell lipid trafficking.Mol. Cell. Endocrinol. 2010; 318: 24-33Crossref PubMed Scopus (67) Google Scholar while RA promoted the loading of both drugs (Figures S17C and S17D). The stability of pDox within [email protected] was evaluated, indicating that pDox was not converted to Dox within 72 h (Figure S14B). The endosome was also labeled, indicating that pDox was preferentially localized in the lipid droplets (Figure S18A). We co-cultured pDox + [email protected] and Dox + [email protected] with B16F10 cells and used murine dermal fibroblasts as a control to compare drug-release profiles and lipolysis. B16F10 significantly triggered the release of Dox (Figure 3D) and pDox (Figure 3E) from adipocytes, while murine fibroblasts did not alter the release profile of both drugs. Furthermore, B16F10 induced lipolysis in adipocytes as indicated by the release of free fatty acids in the media, while fibroblasts did not trigger the lipid release (Figure 3F). However, more pDox tended to be accumulated in the lipid droplets compared with Dox, which exhibited a higher accumulation in the cell nucleus (Figure S18B). Therefore, more pDox was released from adipocytes compared with Dox after 72 h. The hydrogel formulated by fibrin did not affect the release profile of pDox within [email protected] triggered by B16F10 (Figure S17E). In agreement with previous studies,28Sakuma S. Nishioka Y. Imanishi R. Nishikawa K. Sakamoto H. Fujisawa J. Wada K. Kamisaki Y. Fujimoto Y. Cis9, trans11-conjugated linoleic acid differentiates mouse 3T3-L1 preadipocytes into mature small adipocytes through induction of peroxisome proliferator-activated receptor gamma.J. Clin. Biochem. Nutr. 2010; 47: 167-173Crossref PubMed Scopus (16) Google Scholar, 29den Hartigh L.J. Han C.Y. Wang S. Omer M. Chait A. 10E,12Z-conjugated linoleic acid impairs adipocyte triglyceride storage by enhancing fatty acid oxidation, lipolysis, and mitochondrial reactive oxygen species.J. Lipid Res. 2013; 54: 2964-2978Crossref PubMed Scopus (35) Google Scholar RA promoted lipid accumulation in the lipid droplets in 3T3-L1 cells (Figures 3G, 3I, S17A, and S17B). pDox + [email protected] exhibited enhanced cytotoxicity to cancer cells compared with [email protected], and this effect was eliminated by blocking FABP4 (Figure 3H). In the same transwell system, RA encapsulation promoted pDox uptake in adipocytes and B16F10 cells, while the uptake of pDox by B16F10 was inhibited by iFABP4 (Figure 3J). The transportation of lipids from adipocytes to cancer cells was further confirmed by western blot (Figure S17F). Collectively, these data demonstrate that pDox can be effectively loaded into adipocytes and that pDox can be transferred to the tumor cells via lipid transportation and activation of lipolysis. To validate the therapeutic effects of pDox + [email protected] in vivo, we utilized the B16F10 mouse melanoma model. pDox exhibited enhanced antitumor efficacy when delivered by adipocytes compared with free pDox loaded in the fibrin gel (Figures 4A, 4B , and S19A). Survival of mice receiving the pDox + [email protected] was significantly enhanced (Figures 4C, S19A, and S19B) without evident toxicity (Figure S19C). When we analyzed the tumors collected 2 days after the second treatment, mice treated with normally differentiated adipocytes exhibited slightly enhanced expression of PD-L1 in tumor cells (Figures 4D and S20A). We also observed decreased PD-L1 expression in tumor cells (Figures 4D and S20A), increased tumor-infiltrating CD4+ T cells (Figures 4E and S20B) and CD8+ T cells (Figures 4F and S20B), and reduced Tregs infiltration (Figures 4G and S20C) after pDox + [email protected] treatment. These results were confirmed by immunofluorescence and immunohistochemistry staining showing enhanced T cell infiltration (Figures 4H and S20D) and tumor cell apoptosis (Figures 4I and S21). pDox + [email protected] also protected mice from tumor recurrence in a tumor resection model (Figure S22A). Dox + [email protected] and pDox + [email protected] protected mice from tumor recurrence compared with control treatments (62.5% and 37.5%, respectively) (Figures S22B–S22D). Enhanced tumor cell death was achieved in Dox + [email protected] and pDox + [email protected] groups (Figure S24) without detectable toxicity (Figures S22E and S25). Of note, fibrin-loaded RA-treated groups exhibited significantly decreased PD-L1 expression in tumor cells, whereas RA-loaded adipocytes showed enhanced outcomes (Figures S22F and S23A). Meanwhile, the frequencies of CD4+ (Figures S22G and S23B) and CD8+ T cells (Figures S22H and S23B) were significantly enhanced, while a significant decrease of the Treg population was observed (Figures S22I and S23C). These results were further confirmed by immunofluorescence staining, showing enhanced T cell infiltration (Figure S23D), especially in Dox + [email protected] and pDox + [email protected] groups. Recent decades have witnessed fast development of cell therapy using cells or cell-derived particles as drug delivery systems due to their unique transport process and intrinsic properties that facilitate drug delivery.30Chen Z. Wang Z. Gu Z. Bioinspired and biomimetic nanomedicines.Acc. Chem. Res. 2019; 52: 1255-1264PubMed Google Scholar These drug delivery platforms, including erythrocytes,31Wang C. Ye Y. Sun W. Yu J. Wang J. Lawrence D.S. Buse J.B. Gu Z. Red blood cells for glucose-responsive insulin delivery.Adv. Mater. 2017; 29https://doi.org/10.1002/adma.201606617Crossref Scopus (122) Google Scholar, 32Hu C. Zhang L. Aryal S. Cheung C. Fang R. Zhang L. Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic delivery platform.Proceedings of the National Academy of Sciences of the United States of America. 2011; 108: 10980-10985Crossref PubMed Scopus (1422) Google Scholar, 33Yan J. Yu J. Wang C. Gu Z. Red blood cells for drug delivery.Small Methods. 2017; 1: 1700270Crossref Google Scholar platelets,34Hu Q. Sun W. Qian C. Wang C. Bomba H.N. Gu Z. Anticancer platelet-mimicking nanovehicles.Adv. Mater. 2015; 27: 7043-7050Crossref PubMed Scopus (414) Google Scholar, 35Lu Y. Hu Q. Jiang C. Gu Z. Platelet for drug delivery.Curr. Opin. Biotechnol. 2018; 58: 81-91Crossref PubMed Scopus (96) Google Scholar, 36Wang C. Sun W. Ye Y. Bomba H. Gu Z. In situ activation of platelets with checkpoint inhibitors for post-surgical cancer immunotherapy.Nature Biomedical Engineering. 2017; 1: 0011Crossref Scopus (332) Google Scholar and stem cells,37Hu Q. Sun W. Wang J. Ruan H. Zhang X. Ye Y. Shen S. Wang C. Lu W. Cheng K. et al.Conjugation of haematopoietic stem cells and platelets decorated with anti-PD-1 antibodies augments anti-leukaemia efficacy.Nat. Biomed. Eng. 2018; 2: 831-840Crossref PubMed Scopus (162) Google Scholar, 38Tang J. Su T. Huang K. Dinh P.U. Wang Z. Vandergriff A. Hensley M.T. Cores J. Allen T. Li T. et al.Targeted repair of heart injury by stem cells fused with platelet nanovesicles.Nat. Biomed. Eng. 2018; 2: 17-26Crossref PubMed Scopus (117) Google Scholar are mainly administered intravenously due to their long circulation or targeting capabilities to the tumor or inflammatory sites. For solid tumors, surgical resection of primary tumors combined with chemotherapy, radiotherapy, or immunotherapy remains the main option.39Wen D. Chen G. Chen Q. Li P.Y. Cheng H. Gu Z. Engineering protein delivery depots for cancer immunotherapy.Bioconjug. Chem. 2019; 30: 515-524Crossref PubMed Scopus (13) Google Scholar The local drug delivery depot with high biocompatibility to the TME is highly desired for clinical applications. Adipocytes are widely present in the human body, and the procedures including isolation, purification, and differentiation of preadipocytes are straightforward and robust. In addition, the lipid droplets accumulated in adipocytes are natural carriers for hydrophobic drugs. The lipolysis triggered by tumor cells can modulate the drug release profile in a TME-associated metabolism-responsive manner. Genetically engineered adipocytes may further serve as therapeutic depots with desired adipokines and/or membrane proteins. In summary, the protumorigenic role of adipocytes can be reverted through “lipid cargo engineering” with integration of anticancer lipid molecules. Antitumor effects mediated by TAAs can be achieved by localized drug delivery to tumor cells exploiting the FABP4-mediated lipid transportation. Furthermore, [email protected] induced an immunogenic tumor phenotype by downregulating PD-L1 expression, allowing infiltration of effector T cells. This adipocyte-mediated drug delivery strategy could be extended to treat a variety of diseases involving the lipid metabolisms. All chemicals were purchased from Sigma-Aldrich and used as received unless otherwise specified. Doxorubicin hydrochloride was purchased from Oakwood Chemical. BMS309403, the FABP4 inhibitor, was purchased from Cayman Chemical. RA (9Z, 11E-CLA) (catalog no. 16413) was purchased from Sigma-Aldrich. Cell lines of 3T3-L1 (CL-173), B16F10 (CRL-6475), A375 (CRL-1619), and MCF-7 (HTB-22), were purchased from the American Type Culture Collection. E0771 cell line (940001) was purchased from CH3 Biosystems. Bioluminescent B16F10 cells (B16F10-luc-GFP) were provided by Dr. Leaf Huang from University of North Carolina at Chapel Hill. B16F10, A375, and MCF-7 cells were cultured in DMEM (Gibco, Invitrogen) with 10% fetal bovine serum (FBS) (Gibco). E0771 cells were cultured in RPMI 164}, number={5}, journal={MATTER}, author={Wen, Di and Wang, Jinqiang and Van Den Driessche, George and Chen, Qian and Zhang, Yuqi and Chen, Guojun and Li, Hongjun and Soto, Jennifer and Liu, Ming and Ohashi, Masao and et al.}, year={2019}, month={Nov}, pages={1203–1214} }
 @misc{zhang_yu_kahkoska_wang_buse_gu_2019, title={Advances in transdermal insulin delivery}, volume={139}, ISSN={["1872-8294"]}, DOI={10.1016/j.addr.2018.12.006}, abstractNote={Insulin therapy is necessary to regulate blood glucose levels for people with type 1 diabetes and commonly used in advanced type 2 diabetes. Although subcutaneous insulin administration via hypodermic injection or pump-mediated infusion is the standard route of insulin delivery, it may be associated with pain, needle phobia, and decreased adherence, as well as the risk of infection. Therefore, transdermal insulin delivery has been widely investigated as an attractive alternative to subcutaneous approaches for diabetes management in recent years. Transdermal systems designed to prevent insulin degradation and offer controlled, sustained release of insulin may be desirable for patients and lead to increased adherence and glycemic outcomes. A challenge for transdermal insulin delivery is the inefficient passive insulin absorption through the skin due to the large molecular weight of the protein drug. In this review, we focus on the different transdermal insulin delivery techniques and their respective advantages and limitations, including chemical enhancers-promoted, electrically enhanced, mechanical force-triggered, and microneedle-assisted methods.}, journal={ADVANCED DRUG DELIVERY REVIEWS}, author={Zhang, Yuqi and Yu, Jicheng and Kahkoska, Anna R. and Wang, Jinqiang and Buse, John B. and Gu, Zhen}, year={2019}, month={Jan}, pages={51–70} }
 @article{chen_chen_chen_shen_zhang_wang_chan_gu_2019, title={Bioresponsive Protein Complex of aPD1 and aCD47 Antibodies for Enhanced Immunotherapy}, volume={19}, ISSN={["1530-6992"]}, DOI={10.1021/acs.nanolett.9b00584}, abstractNote={Despite the promising efficacy of immune checkpoint blockade (ICB) in treating many types of cancers, the clinical benefits have often been restricted by the low objective response rates and systemic immune-related adverse events. Here, a bioresponsive ICB treatment is developed based on the reactive oxygen species (ROS)-sensitive protein complex for controlled sequential release of anti- “don’t eat me” signal antibody (aCD47) and antiprogrammed cell death protein 1 (aPD1), by leveraging the abundant ROS in the tumor microenvironment (TME). These protein complexes can also act as scavengers of ROS in the TME to reverse the immunosuppressive responses, thereby enhancing antitumor efficacy in vivo. In a melanoma cancer model, the synergistic antitumor efficacy was achieved, which was accompanied by enhanced T cell immune responses together with reduced immunosuppressive responses.}, number={8}, journal={NANO LETTERS}, author={Chen, Qian and Chen, Guojun and Chen, Jiawen and Shen, Jingjing and Zhang, Xudong and Wang, Jinqiang and Chan, Amanda and Gu, Zhen}, year={2019}, month={Aug}, pages={4879–4889} }
 @article{wang_yu_zhang_zhang_kahkoska_chen_wang_sun_cai_chen_et al._2019, title={Charge-switchable polymeric complex for glucose-responsive insulin delivery in mice and pigs}, volume={5}, ISSN={["2375-2548"]}, DOI={10.1126/sciadv.aaw4357}, abstractNote={A glucose-responsive insulin-polymer complex for self-regulated insulin release has been verified in diabetic mice and minipigs.}, number={7}, journal={SCIENCE ADVANCES}, author={Wang, Jinqiang and Yu, Jicheng and Zhang, Yuqi and Zhang, Xudong and Kahkoska, Anna R. and Chen, Guojun and Wang, Zejun and Sun, Wujin and Cai, Lulu and Chen, Zhaowei and et al.}, year={2019}, month={Jul} }
 @article{wang_yu_zhang_kahkoska_wang_fang_whitelegge_li_buse_gu_2019, title={Glucose transporter inhibitor-conjugated insulin mitigates hypoglycemia}, volume={116}, ISSN={["0027-8424"]}, DOI={10.1073/pnas.1901967116}, abstractNote={Significance Glucose-responsive insulin analogs or delivery systems are desirable for enhancing health and improving quality of life of people with diabetes. We describe here a simple strategy to engineer a long-acting insulin analog, which can establish an endogenous Glut-associated delivery reservoir of insulin that can modulate glucose metabolism in a blood glucose-dependent manner. Importantly, after subcutaneous injection, in vivo blood glucose regulation was validated in a type 1 diabetic mouse model with negligible hypoglycemia.}, number={22}, journal={PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}, author={Wang, Jinqiang and Yu, Jicheng and Zhang, Yuqi and Kahkoska, Anna R. and Wang, Zejun and Fang, Jun and Whitelegge, Julian P. and Li, Song and Buse, John B. and Gu, Zhen}, year={2019}, month={May}, pages={10744–10748} }
 @article{chen_wang_zhang_chen_hu_li_wang_wen_zhang_lu_et al._2019, title={In situ sprayed bioresponsive immunotherapeutic gel for post-surgical cancer treatment}, volume={14}, ISSN={["1748-3395"]}, DOI={10.1038/s41565-018-0319-4}, abstractNote={Cancer recurrence after surgical resection remains a significant cause of treatment failure. Here, we have developed an in situ formed immunotherapeutic bioresponsive gel that controls both local tumour recurrence after surgery and development of distant tumours. Briefly, calcium carbonate nanoparticles pre-loaded with the anti-CD47 antibody are encapsulated in the fibrin gel and scavenge H+ in the surgical wound, allowing polarization of tumour-associated macrophages to the M1-like phenotype. The released anti-CD47 antibody blocks the ‘don’t eat me’ signal in cancer cells, thereby increasing phagocytosis of cancer cells by macrophages. Macrophages can promote effective antigen presentation and initiate T cell mediated immune responses that control tumour growth. Our findings indicate that the immunotherapeutic fibrin gel ‘awakens’ the host innate and adaptive immune systems to inhibit both local tumour recurrence post surgery and potential metastatic spread. A gel with therapeutic nanoformulation that can be sprayed at the tumour resection site after surgery activates immune response in the tissue microenviroment, inhibiting tumour recurrence and potential metastasis.}, number={1}, journal={NATURE NANOTECHNOLOGY}, author={Chen, Qian and Wang, Chao and Zhang, Xudong and Chen, Guojun and Hu, Quanyin and Li, Hongjun and Wang, Jinqiang and Wen, Di and Zhang, Yuqi and Lu, Yifei and et al.}, year={2019}, month={Jan}, pages={89-+} }
 @article{yan_zhang_liu_ye_yu_chen_wang_zhang_hu_kang_et al._2019, title={Shape-controlled synthesis of liquid metal nanodroplets for photothermal therapy}, volume={12}, ISSN={["1998-0000"]}, DOI={10.1007/s12274-018-2262-y}, number={6}, journal={NANO RESEARCH}, author={Yan, Junjie and Zhang, Xudong and Liu, Yang and Ye, Yanqi and Yu, Jicheng and Chen, Qian and Wang, Jinqiang and Zhang, Yuqi and Hu, Quanyin and Kang, Yang and et al.}, year={2019}, month={Jun}, pages={1313–1320} }
 @article{ye_wang_sun_bomba_gu_2019, title={Topical and Transdermal Nanomedicines for Cancer Therapy}, volume={5}, ISBN={["978-3-030-01773-6"]}, ISSN={["2364-1126"]}, DOI={10.1007/978-3-030-01775-0_10}, abstractNote={Topical and transdermal nanomedicine systems have attracted considerable attention in anticancer therapy. The administration route toward the skin can transport active drugs through the skin barrier and control their entrance into the blood circulation system. Agents delivered through this platform are capable of escaping the first pass of metabolism, which causes physiological degradation of the agent and systemic clearance. Apart from methodology to facilitate the delivery of drug transdermally, the formulation of nanomedicines to preserve the therapeutic’s property is also critical for overall clinical outcomes. This strategy improves the efficiency of encapsulated drugs by potentiating the targeting capability and tailoring the release kinetics toward specific tumors. This chapter summarizes the principles and the recent innovations in the field of transdermal nanomedicine together with opportunities and challenges in clinical translation. For the continued development of novel transdermal devices incorporating nanotechnology, a deeper understanding is required in rational nanoparticle design and their pharmacokinetics.}, journal={NANOTHERANOSTICS FOR CANCER APPLICATIONS}, author={Ye, Yanqi and Wang, Jinqiang and Sun, Wujin and Bomba, Hunter N. and Gu, Zhen}, year={2019}, pages={231–251} }
 @article{zhang_wang_yu_wen_kahkoska_lu_zhang_buse_gu_2018, title={Bioresponsive Microneedles with a Sheath Structure for H2O2 and pH Cascade-Triggered Insulin Delivery}, volume={14}, ISSN={["1613-6829"]}, DOI={10.1002/smll.201704181}, abstractNote={Self-regulating glucose-responsive insulin delivery systems have great potential to improve clinical outcomes and quality of life among patients with diabetes. Herein, an H2O2-labile and positively charged amphiphilic diblock copolymer is synthesized, which is subsequently used to form nano-sized complex micelles (NCs) with insulin and glucose oxidase of pH-tunable negative charges. Both NCs are loaded into the crosslinked core of a microneedle array patch for transcutaneous delivery. The microneedle core is additionally coated with a thin sheath structure embedding H2O2-scavenging enzyme to mitigate the injury of H2O2 toward normal tissues. The resulting microneedle patch can release insulin with rapid responsiveness under hyperglycemic conditions owing to an oxidative and acidic environment because of glucose oxidation, and can therefore effectively regulate blood glucose levels within a normal range on a chemically induced type 1 diabetic mouse model with enhanced biocompatibility.}, number={14}, journal={SMALL}, author={Zhang, Yuqi and Wang, Jinqiang and Yu, Jicheng and Wen, Di and Kahkoska, Anna R. and Lu, Yue and Zhang, Xudong and Buse, John B. and Gu, Zhen}, year={2018}, month={Apr} }
 @article{tang_wang_huang_ye_su_qiao_hensley_caranasos_zhang_gu_et al._2018, title={Cardiac cell-integrated microneedle patch for treating myocardial infarction}, volume={4}, ISSN={["2375-2548"]}, url={https://doi.org/10.1126/sciadv.aat9365}, DOI={10.1126/sciadv.aat9365}, abstractNote={A microneedle cardiac stromal cell patch has been developed for therapeutic heart regeneration after myocardial infarction.}, number={11}, journal={SCIENCE ADVANCES}, publisher={American Association for the Advancement of Science (AAAS)}, author={Tang, Junnan and Wang, Jinqiang and Huang, Ke and Ye, Yanqi and Su, Teng and Qiao, Li and Hensley, Michael Taylor and Caranasos, Thomas George and Zhang, Jinying and Gu, Zhen and et al.}, year={2018}, month={Nov} }
 @article{hu_sun_wang_ruan_zhang_ye_shen_wang_lu_cheng_et al._2018, title={Conjugation of haematopoietic stem cells and platelets decorated with anti-PD-1 antibodies augments anti-leukaemia efficacy}, volume={2}, ISSN={["2157-846X"]}, DOI={10.1038/s41551-018-0310-2}, abstractNote={Patients with acute myeloid leukaemia who relapse following therapy have few treatment options and face poor outcomes. Immune checkpoint inhibition, for example, by antibody-mediated programmed death-1 (PD-1) blockade, is a potent therapeutic modality that improves treatment outcomes in acute myeloid leukaemia. Here, we show that systemically delivered blood platelets decorated with anti-PD-1 antibodies (aPD-1) and conjugated to haematopoietic stem cells (HSCs) suppress the growth and recurrence of leukaemia in mice. Following intravenous injection into mice bearing leukaemia cells, the HSC-platelet-aPD-1 conjugate migrated to the bone marrow and locally released aPD-1, significantly enhancing anti-leukaemia immune responses, and increasing the number of active T cells, production of cytokines and chemokines, and survival time of the mice. This cellular conjugate also promoted resistance to re-challenge with leukaemia cells. Taking advantage of the homing capability of HSCs and in situ activation of platelets for the enhanced delivery of a checkpoint inhibitor, this cellular combination-mediated drug delivery strategy can significantly augment the therapeutic efficacy of checkpoint blockade.}, number={11}, journal={NATURE BIOMEDICAL ENGINEERING}, author={Hu, Quanyin and Sun, Wujin and Wang, Jinqiang and Ruan, Huitong and Zhang, Xudong and Ye, Yanqi and Shen, Song and Wang, Chao and Lu, Weiyue and Cheng, Ke and et al.}, year={2018}, month={Nov}, pages={831–840} }
 @article{zhang_wang_chen_hu_wang_yan_dotti_huang_gu_2018, title={Engineering PD-1-Presenting Platelets for Cancer Immunotherapy}, volume={18}, ISSN={["1530-6992"]}, DOI={10.1021/acs.nanolett.8b02321}, abstractNote={Radical surgery still represents the treatment choice for several malignancies. However, local and distant tumor relapses remain the major causes of treatment failure, indicating that a postsurgery consolidation treatment is necessary. Immunotherapy with checkpoint inhibitors has elicited impressive clinical responses in several types of human malignancies and may represent the ideal consolidation treatment after surgery. Here, we genetically engineered platelets from megakaryocyte (MK) progenitor cells to express the programmed cell death protein 1 (PD-1). The PD-1 platelet and its derived microparticle could accumulate within the tumor surgical wound and revert exhausted CD8+ T cells, leading to the eradication of residual tumor cells. Furthermore, when a low dose of cyclophosphamide (CP) was loaded into PD-1-expressing platelets to deplete regulatory T cells (Tregs), an increased frequency of reinvigorated CD8+ lymphocyte cells was observed within the postsurgery tumor microenvironment, directly preventing tumor relapse.}, number={9}, journal={NANO LETTERS}, author={Zhang, Xudong and Wang, Jinqiang and Chen, Zhaowei and Hu, Quanyin and Wang, Chao and Yan, Junjie and Dotti, Gianpietro and Huang, Peng and Gu, Zhen}, year={2018}, month={Sep}, pages={5716–5725} }
 @article{wang_wang_zhang_yu_wen_hu_ye_bomba_hu_liu_et al._2018, title={In situ formed reactive oxygen species-responsive scaffold with gemcitabine and checkpoint inhibitor for combination therapy}, volume={10}, ISSN={["1946-6242"]}, DOI={10.1126/scitranslmed.aan3682}, abstractNote={A ROS-responsive hydrogel scaffold controls release of gemcitabine and immune checkpoint inhibitor for enhanced antitumor activity.}, number={429}, journal={SCIENCE TRANSLATIONAL MEDICINE}, author={Wang, Chao and Wang, Jinqiang and Zhang, Xudong and Yu, Shuangjiang and Wen, Di and Hu, Quanyin and Ye, Yanqi and Bomba, Hunter and Hu, Xiuli and Liu, Zhuang and et al.}, year={2018}, month={Feb} }
 @article{zhang_wang_wang_hu_langworthy_ye_sun_lin_wang_fine_et al._2018, title={PD-1 Blockade Cellular Vesicles for Cancer Immunotherapy}, volume={30}, ISSN={["1521-4095"]}, DOI={10.1002/adma.201707112}, abstractNote={Cancer cells resist to the host immune antitumor response via multiple suppressive mechanisms, including the overexpression of PD-L1 that exhausts antigen-specific CD8+ T cells through PD-1 receptors. Checkpoint blockade antibodies against PD-1 or PD-L1 have shown unprecedented clinical responses. However, limited host response rate underlines the need to develop alternative engineering approaches. Here, engineered cellular nanovesicles (NVs) presenting PD-1 receptors on their membranes, which enhance antitumor responses by disrupting the PD-1/PD-L1 immune inhibitory axis, are reported. PD-1 NVs exhibit a long circulation and can bind to the PD-L1 on melanoma cancer cells. Furthermore, 1-methyl-tryptophan, an inhibitor of indoleamine 2,3-dioxygenase can be loaded into the PD-1 NVs to synergistically disrupt another immune tolerance pathway in the tumor microenvironment. Additionally, PD-1 NVs remarkably increase the density of CD8+ tumor infiltrating lymphocytes in the tumor margin, which directly drive tumor regression.}, number={22}, journal={ADVANCED MATERIALS}, author={Zhang, Xudong and Wang, Chao and Wang, Jinqiang and Hu, Quanyin and Langworthy, Benjamin and Ye, Yanqi and Sun, Wujin and Lin, Jing and Wang, Tianfu and Fine, Jason and et al.}, year={2018}, month={May} }
 @article{ma_xiao_yu_liu_cheng_song_zhang_li_wang_gu_et al._2017, title={Enhanced Cisplatin Chemotherapy by Iron Oxide Nanocarrier-Mediated Generation of Highly Toxic Reactive Oxygen Species}, volume={17}, ISSN={["1530-6992"]}, DOI={10.1021/acs.nanolett.6b04269}, abstractNote={Reactive oxygen species (ROS) plays a key role in therapeutic effects as well as side effects of platinum drugs. Cisplatin mediates activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), which triggers oxygen (O2) to superoxide radical (O2•-) and its downstream H2O2. Through the Fenton's reaction, H2O2 could be catalyzed by Fe2+/Fe3+ to the toxic hydroxyl radicals (•OH), which cause oxidative damages to lipids, proteins, and DNA. By taking the full advantage of Fenton's chemistry, we herein demonstrated tumor site-specific conversion of ROS generation induced by released cisplatin and Fe2+/Fe3+ from iron-oxide nanocarriers with cisplatin(IV) prodrugs for enhanced anticancer activity but minimized systemic toxicity.}, number={2}, journal={NANO LETTERS}, author={Ma, Ping'an and Xiao, Haihua and Yu, Chang and Liu, Jianhua and Cheng, Ziyong and Song, Haiqin and Zhang, Xinyang and Li, Chunxia and Wang, Jinqiang and Gu, Zhen and et al.}, year={2017}, month={Feb}, pages={928–937} }
 @article{yu_zhang_sun_kahkoska_wang_buse_gu_2017, title={Insulin-responsive glucagon delivery for prevention of hypoglycemia}, volume={13}, DOI={10.1002/smll.201770108}, number={19}, journal={Small (Weinheim An Der Bergstrasse, Germany)}, author={Yu, J. C. and Zhang, Y. Q. and Sun, W. J. and Kahkoska, A. R. and Wang, J. Q. and Buse, J. B. and Gu, Z.}, year={2017} }
 @article{zhang_liu_yu_yu_wang_qiang_gu_2017, title={Locally Induced Adipose Tissue Browning by Microneedle Patch for Obesity Treatment}, volume={11}, ISSN={["1936-086X"]}, DOI={10.1021/acsnano.7b04348}, abstractNote={Obesity is one of the most serious public health problems in the 21st century that may lead to many comorbidities such as type-2 diabetes, cardiovascular diseases, and cancer. Current treatments toward obesity including diet, physical exercise, pharmacological therapy, as well as surgeries are always associated with low effectiveness or undesired systematical side effects. In order to enhance treatment efficiency with minimized side effects, we developed a transcutaneous browning agent patch to locally induce adipose tissue transformation. This microneedle-based patch can effectively deliver browning agents to the subcutaneous adipocytes in a sustained manner and switch on the “browning” at the targeted region. It is demonstrated that this patch reduces treated fat pad size, increases whole body energy expenditure, and improves type-2 diabetes in vivo in a diet-induced obesity mouse model.}, number={9}, journal={ACS NANO}, author={Zhang, Yuqi and Liu, Qiongming and Yu, Jicheng and Yu, Shuangjiang and Wang, Jinqiang and Qiang, Li and Gu, Zhen}, year={2017}, month={Sep}, pages={9223–9230} }
 @article{wang_ye_sun_yu_wang_lawrence_buse_gu_2017, title={Red Blood Cells for Glucose-Responsive Insulin Delivery}, volume={29}, ISSN={["1521-4095"]}, DOI={10.1002/adma.201606617}, abstractNote={Glucose-responsive delivery of insulin mimicking the function of pancreatic β-cells to achieve meticulous control of blood glucose (BG) would revolutionize diabetes care. Here the authors report the development of a new glucose-responsive insulin delivery system based on the potential interaction between the glucose derivative-modified insulin (Glc-Insulin) and glucose transporters on erythrocytes (or red blood cells, RBCs) membrane. After being conjugated with the glucosamine, insulin can efficiently bind to RBC membranes. The binding is reversible in the setting of hyperglycemia, resulting in fast release of insulin and subsequent drop of BG level in vivo. The delivery vehicle can be further simplified utilizing injectable polymeric nanocarriers coated with RBC membrane and loaded with Glc-Insulin. The described work is the first demonstration of utilizing RBC membrane to achieve smart insulin delivery with fast responsiveness.}, number={18}, journal={ADVANCED MATERIALS}, author={Wang, Chao and Ye, Yanqi and Sun, Wujin and Yu, Jicheng and Wang, Jingqiang and Lawrence, David S. and Buse, John B. and Gu, Zhen}, year={2017}, month={May} }
 @article{chen_wang_sun_archibong_kahkoska_zhang_lu_ligler_buse_gu_2017, title={Synthetic beta cells for fusion-mediated dynamic insulin secretion}, volume={14}, ISSN={1552-4450 1552-4469}, url={http://dx.doi.org/10.1038/NCHEMBIO.2511}, DOI={10.1038/nchembio.2511}, abstractNote={Synthetic beta cells were fabricated through 'vesicles-in-vesicle' liposomal superstructures equipped with glucose-sensing and membrane-fusion machinery, thus enabling sensing of graded glucose levels and secretion of insulin via fusion processes. Generating artificial pancreatic beta cells by using synthetic materials to mimic glucose-responsive insulin secretion in a robust manner holds promise for improving clinical outcomes in people with diabetes. Here, we describe the construction of artificial beta cells (AβCs) with a multicompartmental 'vesicles-in-vesicle' superstructure equipped with a glucose-metabolism system and membrane-fusion machinery. Through a sequential cascade of glucose uptake, enzymatic oxidation and proton efflux, the AβCs can effectively distinguish between high and normal glucose levels. Under hyperglycemic conditions, high glucose uptake and oxidation generate a low pH (<5.6), which then induces steric deshielding of peptides tethered to the insulin-loaded inner small liposomal vesicles. The peptides on the small vesicles then form coiled coils with the complementary peptides anchored on the inner surfaces of large vesicles, thus bringing the membranes of the inner and outer vesicles together and triggering their fusion and insulin 'exocytosis'.}, number={1}, journal={Nature Chemical Biology}, publisher={Springer Science and Business Media LLC}, author={Chen, Zhaowei and Wang, Jinqiang and Sun, Wujin and Archibong, Edikan and Kahkoska, Anna R and Zhang, Xudong and Lu, Yue and Ligler, Frances S and Buse, John B and Gu, Zhen}, year={2017}, month={Oct}, pages={86–93} }
 @article{hu_qian_sun_wang_chen_bomba_xin_shen_gu_2016, title={Engineered Nanoplatelets for Enhanced Treatment of Multiple Myeloma and Thrombus}, volume={28}, ISSN={["1521-4095"]}, DOI={10.1002/adma.201603463}, abstractNote={A platelet-membrane-coated biomimetic nanocarrier, which can sequentially target the bone microenvironment and myeloma cells to enhance the drug availability at the myeloma site and decrease off-target effects, is developed for inhibiting multiple myeloma growth and simultaneously eradicating thrombus complication.}, number={43}, journal={ADVANCED MATERIALS}, author={Hu, Quanyin and Qian, Chenggen and Sun, Wujin and Wang, Jinqiang and Chen, Zhaowei and Bomba, Hunter N. and Xin, Hongliang and Shen, Qundong and Gu, Zhen}, year={2016}, month={Nov}, pages={9573-+} }
 @article{ye_wang_hu_hochu_xin_wang_gu_2016, title={Synergistic Transcutaneous Immunotherapy Enhances Antitumor Immune Responses through Delivery of Checkpoint Inhibitors}, volume={10}, ISSN={["1936-086X"]}, DOI={10.1021/acsnano.6b04989}, abstractNote={Despite the promising efficacy of immunoregulation in cancer therapy, the clinical benefit has been restricted by inefficient infiltration of lymphocytes in the evolution of immune evasion. Also, immune-related adverse events have often occurred due to the off-target binding of therapeutics to normal tissues after systematic treatment. In light of this, we have developed a synergistic immunotherapy strategy that locally targets the immunoinhibitory receptor programmed cell death protein 1 (PD1) and immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) for the treatment of melanoma through a microneedle-based transcutaneous delivery approach. The embedded immunotherapeutic nanocapsule loaded with anti-PD1 antibody (aPD1) is assembled from hyaluronic acid modified with 1-methyl-dl-tryptophan (1-MT), an inhibitor of IDO. This formulation method based on the combination strategy of "drug A in carriers formed by incorporation of drug B" facilitates the loading capacity of therapeutics. Moreover, the resulting delivery device elicits the sustained release and enhances retention of checkpoint inhibitors in the tumor microenvironment. Using a B16F10 mouse melanoma model, we demonstrate that this synergistic treatment has achieved potent antitumor efficacy, which is accompanied by enhanced effective T cell immunity as well as reduced immunosuppression in the local site.}, number={9}, journal={ACS NANO}, author={Ye, Yanqi and Wang, Jinqiang and Hu, Quanyin and Hochu, Gabrielle M. and Xin, Hongliang and Wang, Chao and Gu, Zhen}, year={2016}, month={Sep}, pages={8956–8963} }
 @article{wang_ye_yu_kahkoska_zhang_wang_sun_corder_chen_khan_et al., title={Core-Shell Microneedle Gel for Self-Regulated Insulin Delivery}, volume={12}, number={3}, journal={ACS Nano}, author={Wang, J. Q. and Ye, Y. Q. and Yu, J. C. and Kahkoska, A. R. and Zhang, X. D. and Wang, C. and Sun, W. J. and Corder, R. D. and Chen, Z. W. and Khan, S. A. and et al.}, pages={2466–2473} }