Abstract

Abstract The highly immunosuppressive tumor microenvironment (TME) in solid tumors often dampens the efficacy of immunotherapy. In this study, bacterial outer membrane vesicles (OMVs) are demonstrated as powerful immunostimulants for TME reprogramming. To overcome the obstacles of antibody‐dependent clearance and high toxicity induced by OMVs upon intravenous injection (a classic clinically relevant delivery mode), calcium phosphate (CaP) shells are employed to cover the surface of OMVs, which enables potent OMV‐based TME reprograming without side effects. Meanwhile, the pH‐sensitive CaP shells facilitate the neutralization of acidic TME, leading to highly beneficial M2‐to‐M1 polarization of macrophages for improved antitumor effect. Moreover, the outer shells can be integrated with functional components like folic acid or photosensitizer agents, which facilitates the use of the OMV‐based platform in combination therapies for a synergic therapeutic effect.