The success of checkpoint inhibitors in cancer treatment is associated with the infiltration of tissue-resident memory T (Trm) cells. In this study, we found that about 30% of tumor-infiltrating lymphocytes (TIL) in the tumor microenvironment of gastric adenocarcinoma were CD69+CD103+ Trm cells. Trm cells were low in patients with metastasis, and the presence of Trm cells was associated with better prognosis in patients with gastric adenocarcinoma. Trm cells expressed high PD-1, TIGIT, and CD39 and represented tumor-reactive TILs. Instead of utilizing glucose, Trm cells relied on fatty acid oxidation for cell survival. Deprivation of fatty acid resulted in Trm cell death. In a tumor cell–T-cell coculture system, gastric adenocarcinoma cells outcompeted Trm cells for lipid uptake and induced Trm cell death. Targeting PD-L1 decreased fatty acid binding protein (Fabp) 4 and Fabp5 expression in tumor cells of gastric adenocarcinoma. In contrast, the blockade of PD-L1 increased Fabp4/5 expression in Trm cells, promoting lipid uptake by Trm cells and resulting in better survival of Trm cells in vitro and in vivo. PD-L1 blockade unleashed Trm cells specifically in the patient-derived xenograft (PDX) mice. PDX mice that did not respond to PD-L1 blockade had less Trm cells than responders. Together, these data demonstrated that Trm cells represent a subset of TILs in the antitumor immune response and that metabolic reprogramming could be a promising way to prolong the longevity of Trm cells and enhance antitumor immunity in gastric adenocarcinoma.

Glucose-responsive insulin delivery systems show great promise to improve therapeutic outcomes and quality of life for people with diabetes. Herein, a new microneedle-array patch containing pH-sensitive insulin-loaded nanoparticles (NPs) (SNP(I)) together with glucose oxidase (GOx)- and catalase (CAT)-loaded pH-insensitive NPs (iSNP(G+C)) is constructed for transcutaneous glucose-responsive insulin delivery. SNP(I) are prepared via double emulsion from a pH-sensitive amphiphilic block copolymer, and undergo rapid dissociation to promote insulin release at a mild acidic environment induced by GOx in iSNP(G+C) under hyperglycemic conditions. CAT in iSNP(G+C) can further consume excess H₂O₂ generated during GOx oxidation, and thus reduce the risk of inflammation toward the normal skin. The in vivo study on type 1 diabetic mice demonstrates that the platform can effectively regulate blood glucose levels within normal ranges for a prolonged period.

Non-specific surface adsorption of bio-macromolecules (e.g. proteins) on nanoparticles, known as biofouling, and the uptake of nanoparticles by the mononuclear phagocyte system (MPS) and reticuloendothelial system (RES) lead to substantial reduction in the efficiency of target-directed imaging and delivery in biomedical applications of engineered nanomaterials in vitro and in vivo. In this work, a novel copolymer consisting of blocks of poly ethylene glycol and allyl glycidyl ether (PEG-b-AGE) was developed for coating magnetic iron oxide nanoparticles (IONPs) to reduce non-specific protein adhesion that leads to formation of “protein corona” and uptake by macrophages. The facile surface functionalization was demonstrated by using targeting ligands of a small peptide of RGD or a whole protein of transferrin (Tf). The PEG-b-AGE coated IONPs exhibited anti-biofouling properties with significantly reduced protein corona formation and non-specific uptake by macrophages before and after the surface functionalization, thus improving targeting of RGD-conjugated PEG-b-AGE coated IONPs to integrins in U87MG glioblastoma and MDA-MB-231 breast cancer cells that overexpress α_vβ₃ integrins, and Tf-conjugated PEG-b-AGE coated IONPs to transferrin receptor (TfR) in D556 and Daoy medulloblastoma cancer cells with high overexpression of transferrin receptor, compared to respective control cell lines. Magnetic resonance imaging (MRI) of cancer cells treated with targeted IONPs with or without anti-biofouling PEG-b-AGE coating polymers demonstrated the target specific MRI contrast change using anti-biofouling PEG-b-AGE coated IONP with minimal off-targeted background compared to the IONPs without anti-biofouling coating, promising the highly efficient active targeting of nanoparticle imaging probes and drug delivery systems and potential applications of imaging quantification of targeted biomarkers.

A polyethylenimine based diazeniumdiolate nitric oxide donor was prepared to accelerate wound healing.