Engineered bacterial outer membrane vesicles integrated with photothermal therapy: disrupting the CD47-SIRPα axis to enhance pyroptosis and antitumor immunity

Bacterial outer membrane vesicles (OMVs) garner significant attention in tumor therapy due to their unique ability to selectively target and eliminate tumor cells. However, tumor cells commonly overexpress CD47, a “don’t eat me” signal that interacts with signal regulatory protein alpha (SIRPα) on macrophages, thus evading immune clearance. Enhancing OMV-induced immunogenicity and reprogramming macrophages toward a pro-phagocytic phenotype while blocking the CD47-SIRPα pathway is essential. In this study, OMVs are engineered to express anti-CD47 antibodies on their surface and are combined with Y18 nanoparticles (NPs) to construct a biomimetic hybrid nanoplatform (Y18-OMV NPs). This dual-functional strategy integrates photothermal design and immune checkpoint blockade to achieve efficient photoimmunotherapy. Photothermal therapy (PTT) induces immunogenic cell death via endoplasmic reticulum stress (eIF2α-ATF4-CHOP pathway) and pyroptosis (NLRP3/Caspase-1/GSDMD axis), releasing damage-associated molecular patterns (DAMPs) to activate immune responses. Simultaneously, Y18-OMV NPs function as immune adjuvants to repolarize M2-like tumor-associated macrophages (TAMs) into the M1 phenotype, enhance macrophage-mediated phagocytosis, promote dendritic cell maturation, and activate T cell infiltration. This strategy also downregulates heat shock proteins (HSPs), reduces thermotolerance, and enhances PTT efficacy. Overall, this approach provides robust photothermal-immunotherapy synergy and offers a promising direction for CD47-targeted clinical tumor immunotherapy. Diagrammatic representation of the preparation of Y18-OMV NPs and their antitumor mechanisms.