Engineered apoptotic vesicle mimetics with tunable "eat-me" signaling precisely regulate tumor-associated macrophages for potentiating cancer immunotherapy

Repolarizing immunosuppressive M2-phenotype tumor-associated macrophages (TAMs) and blocking the CD47/SIRPα axis are promising strategies to enhance cancer immunotherapy. However, non-selective disruption of macrophage phenotypic balance and CD47/SIRPα signaling can lead to immune-related side effects. To address this, we develop a smart biomimetic nanoparticle (PARM) loaded with R848 and manganese ions (Mn2+). PARM is coated with an apoptotic vesicle membrane and a pH-sensitive PEG corona, enabling targeted delivery to TAMs in the acidic tumor microenvironment (TME). The PEG corona protects the nanoparticle from uptake during circulation and sheds in the TME, exposing the apoptotic vesicle membrane. This triggers specific recognition and uptake by TAMs via the "eat-me" signal. R848 and Mn2+ repolarize TAMs into a pro-inflammatory phenotype, while the activation of cGAS-STING pathway by Mn2+ reduces SIRPα expression and enhances TAM phagocytosis. In vivo studies demonstrate that PARM remodels the immunosuppressive TME by repolarizing TAMs and promoting CD8+ T cell infiltration. This leads to significant inhibition of tumor growth and metastasis. These findings highlight the multifaceted role of the cGAS-STING pathway in TAM modulation and present a novel strategy for enhancing macrophage-based cancer immunotherapy.