Multifunctional copper complex-mediated self-blocking plasmid delivery of PD-L1 for tumor chemoimmunotherapy

Copper-based therapeutics can induce the immunogenic death of tumor cells and promote activation of the tumor immune microenvironment, thereby exerting a synergistic effect with PD-1/PD-L1 blockade and enhancing the antitumor immune response. However, adaptive DNA damage repair and inefficient tumor-specific delivery remain major obstacles limiting their therapeutic efficacy. Herein, we developed a homologous tumor cell membrane-camouflaged biomimetic nanoplatform, in which polyethyleneimine (PEI) and Olaparib (Ola) were assembled to construct the nanoparticle framework, enabling Cu²⁺ coordination and pPD-L1 trap plasmid condensation, while conjugation of R15 peptides facilitated nuclear-targeted delivery. The biomimetic nanoplatform utilized homologous tumor cell membrane camouflage to achieve prolonged blood circulation and tumor-targeted delivery in vivo, followed by R15 peptide-guided nuclear translocation, while intracellular Cu²⁺ ions and Ola functioned as Fenton-like reaction inducers and DNA damage aggravators, respectively, thereby enhancing tumor immunogenicity, remodeling the immunosuppressive tumor microenvironment, and synergizing with PD-L1 trap proteins to amplify antitumor immune responses. Collectively, this biomimetic drug delivery system achieved targeted co-delivery of three therapeutic components, effectively exerted their synergistic antitumor effects, and provided a promising strategy for combined chemotherapy and immunotherapy against tumors.