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.

Inspired by the clinically approved albumin based PTX formulation (Abraxane) and high-drug-loading dimeric prodrug tactics, herein we report a theranostic "Abraxane-like" prodrug formulation, which is comprised of human serum albumin (HSA), a paclitaxel (PTX) dimer bridged with thioether liner (PTX₂-S), and photosensitizer IR780 iodide. Nanoparticles (NPs) with PTX₂-S and IR780 as the core and HSA as the stealth shell are formed. Compared with HSA-based PTX clinical formulation (Abraxane), the dimeric molecules not only constitute the bulk structure of the particles, but also act as crossing agent, thus realizing drug loading content increasing from 6.6 wt.% to 48.7 wt.% with high loading efficiency (> 90%) and excellent stability in biological conditions. Importantly, the thioether linkage dually responds to the tumor redox heterogeneity and the NPs gradually releases the parent drug PTX for chemotherapy. Meanwhile, PTX₂-S facilitates the encapsulation of IR780 iodide due to their π-π stacking interaction and IR780 iodide generates spatio-temporal hyperthermia under light irradiation to kill cancer cells for photothermal therapy. The described craft integrates the biomimetic trait of HSA, high drug loading, tumor redox heterogeneity- initiated on-demand drug release, and combination therapy into one formulation and the developed nanoparticles are promising for cancer treatment.