Copackaging Doxorubicin and PD‐L1 siRNA in Dual‐Responsive Covalent Organic Frameworks for Synergistic Cancer Chemoimmunotherapy

Abstract Chemoimmunotherapy, which integrates chemotherapeutic drugs with immune modulators, has emerged as a promising approach to enhance the generally lackluster clinical outcomes of immunotherapy. Nevertheless, a significant challenge lies in orchestrating multiple events associated with diverse mechanisms that activate antitumor immune responses. Here, a novel approach utilizing dual‐responsive covalent organic frameworks (COFs) co‐encapsulating doxorubicin (DOX) and programmed cell death ligand‐1 (PD‐L1) siRNA (siPD‐L1), termed RDAP, is presented for synergistic chemoimmunotherapy. In this system, COFs modified with poly‐L‐lysine (PLL) can adsorb DOX within their porous structure and bind siPD‐L1 onto their surface via electrostatic interactions. The resulting RDAP formulation can escape from lysosome via the “proton sponge effect” and undergo rupture upon exposure to azoreductase, leading to the efficient release of DOX and siPD‐L1 into the cytoplasm of 4T1 cells. The RDAP, harboring dual therapeutic agents, can effectively eliminate tumor cells and trigger significant immunogenic cell death (ICD) through DOX. Additionally, it concomitantly suppresses PD‐L1 expression in tumor cells, thereby significantly enhancing the antitumor immune response and resulting in synergistically improved antitumor efficacy. In mouse models, RDAP demonstrated exceptional efficacy in eliminating both primary and distant tumors, along with a pronounced antimetastatic effect against 4T1 murine breast‐to‐lung metastasis.