Biomimetic nanoplatform potentiates STING-immunotherapy by coordinated delivery of chemotherapeutic and innate immune agonist

Assembly of tumor cell membrane–cloaked PEG–PLGA@DOX/R848 and schematic of dual cGAS–STING/TLR7/8 activation to remodel the tumor immune microenvironment and potentiate chemo-immunotherapy in TNBC. Triple-negative breast cancer (TNBC) lacks effective targeted therapies, with outcomes limited by an immunosuppressive tumor microenvironment. We developed a tumor cell membrane–cloaked PEG-PLGA nanoplatform that co-delivers doxorubicin (DOX) and the Toll-like receptor 7/8 agonist R848. DOX-induced cytosolic DNA activates the cGAS–STING axis, while R848 engages TLR7/8–MyD88–NF-κB/IRF7 in antigen-presenting cells; their convergence potentiates type-I interferon signaling and immunogenic cell death, repolarizing macrophages from M2 to M1 and promoting effector and memory T-cell responses. In orthotopic and metastatic TNBC models, the platform suppressed tumor growth with favorable tolerability, supporting translational chemoimmunotherapy. • Biomimetic membrane coating confers enhanced tumor targeting and efficient intracellular delivery. • pH-responsive co-release of doxorubicin and a TLR7/8 agonist elicits synergistic tumor cell killing. • Coordinated activation of the cGAS–STING and TLR–MyD88 pathways amplifies type I interferon signaling and antitumor immune responses. An immunosuppressive tumor microenvironment is a major barrier to effective chemoimmunotherapy. In this work, a cancer cell membrane–coated PEG–PLGA nanoparticle system was constructed to co-deliver doxorubicin and the TLR7/8 agonist R848 for coordinated immune activation. The resulting core–shell nanomaterial exhibited pH-responsive behavior and enhanced tumor cellular uptake. In vitro studies showed that treatment induced robust activation of innate immune signaling, including a 2.3-fold increase in IFN-β secretion mediated by the cGAS–STING–IRF3 pathway, together with activation of MyD88–NF-κB signaling. These effects were accompanied by synergistic cytotoxicity (CI < 1), macrophage repolarization toward an M1 phenotype, as reflected by an increase in the IL-12/IL-10 ratio from approximately 0.7 to >3.2, and a pronounced Th1-biased immune response. In orthotopic and experimental metastatic triple-negative breast cancer models, the membrane-coated nanoparticles achieved approximately 75 % inhibition of primary tumor growth and a 95 % reduction in lung metastatic burden, without detectable systemic toxicity. These results demonstrate that biomimetic membrane–assisted co-delivery enables synchronized activation of cytosolic and endosomal innate immune pathways, providing an effective strategy for remodeling the tumor immune microenvironment and enhancing chemoimmunotherapeutic efficacy