Amplifying Synergistic Effects of Cuproptosis and Bacterial Membrane Vesicles‐Mediated Photothermal Therapy by Multifunctional Nano‐Biohybrid for Anti‐Tumor Immunotherapy

Abstract The other functions of bacterial membrane vesicles (BMVs) except serving as immune adjuvants and vaccine platforms are yet to be further explored. This study investigates the photothermal properties of Rhodobacter sphaeroides‐derived BMVs (RMVs) beyond their immunostimulatory properties. A multifunctional nano‐biohybrid, termed CuM@RR, is constructed by encapsulating Cu‐based metal–organic framework (CuM) nanoparticles into DSPE‐PEG₂₀₀₀‐RGD‐functionalized RMVs, leveraging the functionalization and cargo capacity of BMVs. The DSPE‐PEG₂₀₀₀‐RGD modification facilitates the targeted delivery of CuM@RR to tumor sites. CuM core within CuM@RR decomposes in acid tumor microenvironment, releasing Cu²⁺ and inducing tumor cell cuproptosis. Under 808 nm near‐infrared irradiation, the photothermal effect‐induced apoptosis synergizes with copper ions overload‐induced cuproptosis, causing irreversible mitochondrial damage in tumor cells and triggering strong immunogenic cell death (ICD). The released damage‐associated molecular patterns (DAMPs) and tumor‐associated antigens (TAAs) during ICD, along with the inherent immunoadjuvant properties of CuM@RR, elicit robust anti‐tumor immune responses. In vivo experiments confirm that CuM@RR significantly suppresses tumor growth and prevents tumor rechallenge without obvious systemic toxicity under the synergistic effects of cuproptosis, photothermal therapy, and immunotherapy, suggesting the great potential of this multifunctional nano‐biohybrid in developing safe and effective multi‐therapeutic anti‐tumor strategies.