Self‐Assembled Dual‐Drug Nanoparticles for Tumor‐Targeted Delivery and Enhanced Antitumor Chemo‐Immunotherapy

ABSTRACT Insufficient tumor‐targeting accumulation and the immunosuppressive tumor microenvironment (TME) greatly restrict the efficacy of chemo‐immunotherapy. Herein, AWS@PTNC nanoparticles (NPs) are elaborately fabricated via self‐assembly of paclitaxel dimer and serine synthesis inhibitor, followed by surface modification with CD47‐targeting peptide for precise drug delivery and immunosuppressive TME remodeling. Specifically, the nanoplatform could actively accumulate in tumor regions, mediate lysosomal degradation of CD47 via endocytosis to recover the immune activity of M1‐type macrophages. Elevated intracellular redox levels trigger the stimuli‐responsive release of dual drugs, which jointly suppress cell division and lipid metabolism, strengthening direct cytotoxicity against tumor cells. Metabolic remodeling and amplified immunogenic cell death (ICD) further recruit and activate dendritic cells (DCs) and cytotoxic T lymphocytes (CTLs). Benefiting from these synergistic effects, AWS@PTNC NPs fundamentally remodel the immunosuppressive TME, elicit long‐term antitumor immune memory in tumor rechallenge model, and achieve prominent therapeutic efficacy in postoperative recurrence model combined with anti‐SIRPα antibody. This facile and biocompatible nanoplatform holds promising potential for clinical tumor chemo‐immunotherapy.