Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment for their unprecedented clinical efficacy. Signal regulatory protein α (SIRPα) is a phagocytic checkpoint expressed on macrophages, dendritic cells, and other myeloid cells. Cancer cells inhibit macrophage phagocytosis through the interaction of the CD47–SIRPα axis. Disrupting the CD47–SIRPα axis has therefore been a promising strategy in restoring the immune attack against cancer. Herein, we engineered cellular membrane nanovesicles (NVs) presenting SIRPα receptors for phagocytosis checkpoint blockade to augment the antitumor immune response. Furthermore, zebularine (Zeb), an inhibitor of DNA methyltransferase, was encapsulated into SIRPα NVs to reprogram the immunosuppressive tumor microenvironment together with blockade of phagocytosis checkpoint. It is demonstrated that SIRPα@Zeb can improve tumor immunogenicity, the polarization of tumor-associated macrophages to the M1 phenotype, and increase the infiltration of CD8⁺ T lymphocytes in tumors. The robust antitumor immune response induced by SIRPα@Zeb significantly suppressed tumor growth and extended mice-bearing melanoma xenograft survival.

A bioresponsive polymeric nanocarrier for drug delivery is able to alter its physical and physicochemical properties in response to a variety of biological signals and pathological changes, and can exert its therapeutic efficacy within a confined space. These nanosystems can optimize the biodistribution and subcellular location of therapeutics by exploiting the differences in biochemical properties between tumors and normal tissues. Moreover, bioresponsive polymer-based nanosystems could be rationally designed as precision therapeutic platforms by optimizing the combination of responsive elements and therapeutic components according to the patient-specific disease type and stage. In this review, recent advances in smart bioresponsive polymeric nanosystems for cancer chemotherapy and immunotherapy will be summarized. We mainly discuss three categories, including acidity-sensitive, redox-responsive, and enzyme-triggered polymeric nanosystems. The important issues regarding clinical translation such as reproducibility, manufacture, and probable toxicity, are also commented.

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.