A biohybrid platform integrating bacterial propulsion and photoresponsive nanomedicine for adequate intratumoral drug delivery.

Efficient and uniform delivery of nanomedicine into deep tumors remains challenging due to the limited targeting efficiency and the dense stromal barrier of solid tumors. Here, we report a bacterial biohybrid platform that integrates tumor-tropic bacteria with photoresponsive nanomedicine to achieve deep intratumoral drug delivery through active bacterial locomotion, passive nanoparticle diffusion, and photo-controlled spatiotemporal release. This biohybrid is constructed by conjugating attenuated Salmonella typhimurium VNP20009 with polyglycerol-decorated hollow mesoporous ruthenium nanoparticles, which act simultaneously as photothermal agents and nanocarriers co-encapsulating thermosensitive 1-tetradecanol and chemotherapeutic DOXorubicin. Guided by bacterial chemotaxis, the biohybrid actively colonizes the hypoxic and deep tumor regions inaccessible to conventional nanomedicines. Upon near-infrared irradiation, localized photothermal heating detaches nanoparticles from the bacterial surface, converting transport from active bacterial locomotion to passive interstitial diffusion, and simultaneously melts the thermosensitive 1-tetradecanol to trigger pulsatile doxorubicin release. Following nanoparticle detachment, the unmasked bacterial surface engages with host immune cells, promoting macrophage M1 polarization and establishing a pro‑inflammatory tumor microenvironment. This immune activation acts in concert with photothermal therapy and spatiotemporally controlled chemotherapy to synergistically achieve potent photochemo-immunotherapy with minimal systemic toxicity. Overall, this work establishes a generalizable strategy to achieve adequate intratumoral drug delivery and highlights the therapeutic potential of bacteria-mediated hybrid systems.