Outer membrane vesicles-based nano-regulator for cancer immunotherapy by modulating neutrophils N1 polarization and hitchhiking delivery

Efficient eradication of cancer cells and enhanced tumor accumulation of drug via immune cells represent promising strategies for cancer treatment, yet they remain significant challenges. Inspired by neutrophils (NEs), we designed a novel nano-regulator (OMV@PCB NPs) to improve cancer therapy through polarizing NEs into anti-tumor N1 phenotype and photodynamic therapy (PDT)-assisted NEs hitchhiking delivery. OMV@PCB NPs were constructed by encapsulating Ce6 and SB525334 (TGF-β inhibitor) within PLGA nanoparticles, which were subsequently camouflaged with bacteria outer membrane vesicles (OMVs). Beyond inducing ROS generation under light irradiation to kill tumor cells, OMV@PCB NPs could effectively hitchhike NEs to enhance tumor accumulation based on PDT-assisted NEs recruitment. Encouragingly, SB525334, a TGF-β inhibitor in OMV@PCB NPs, could significantly polarize NEs into anti-tumor N1 phenotype, which could not only promote neutrophil elastase (ELANE) release to selectively eliminate cancer cells, but also elevate anticancer immunity by reversing the immunosuppressive tumor microenvironment, thereby achieving effective immuno-photodynamic therapy against tumor growth. This study offers a prospective avenue for enhancing cancer therapy.