An X-ray-activated nano-bio hybrid for synergistic radiotherapy/photothermal/immunotherapy of prostate cancer

Photothermal therapy (PTT) is recognized for its precise manipulability and exceptional spatiotemporal control but faces challenges such as thermotolerance, weak penetration, and collateral tissue damage. Herein, we presented a strategy that enabled tumor-targeted PTT, reduced interstitial fluid pressure (IFP), promoted deep tumor penetration, enhanced radiosensitization, and counteracted thermoresistance. An engineered bacteria-based delivery system (R.S@BiOI) responsive to low-dose X-ray was constructed via electrostatic adsorption of bismuth oxyiodide quantum dots (BiOI QDs) onto the natural photothermal agent Rhodobacter sphaeroides (R.S). Leveraging the hypoxic targeting capability of R.S, R.S@BiOI facilitated tumor-specific enrichment and penetration. Meanwhile, X-ray-triggered radiolysis of water by surface-bound BiOI QDs generated hydroxyl radicals, which reduced tumor IFP, enhanced the deep and uniform distribution of the R.S@BiOI composite, and minimized collateral thermal damage to surrounding healthy tissues. Furthermore, X-ray irradiation downregulated the expression of heat shock proteins, attenuating cellular thermotolerance and synergistically improving the efficacy of PTT. Meanwhile, R.S@BiOI elicited a robust anti-tumor immune response, which acted in synergy with radiotherapy and PTT to potentiate the overall antitumor efficacy. The bacteria-based delivery system enhanced intratumoral accumulation and improved tumor distribution, resulting in markedly superior tumor growth suppression, prolonged survival in animal models, and a well-tolerated safety profile with no significant systemic toxicity observed in critical organs. Thus, this study presents a strategy for fabricating X-ray-responsive engineered bacteria that potentiate the therapeutic efficacy of PTT in the treatment of prostate cancer.