NIR-activated NO-propelled nanomotors for deep tumor penetration and DNA-repair sensitized photothermal therapy of prostate cancer

Abstract Photothermal therapy (PTT) for solid prostate cancer (PCa) is often limited by poor intratumoral penetration and rapid DNA repair. Herein, we engineered a PSMA-targeted gas nanomotor that couple deep tumor penetration with DNA repair sensitization for enhanced photothermal/NO therapy. BLM helicase inhibitor ML216 and nitric oxide donor BNN6 were co-encapsulated with phase-change material and loaded into single-pore hollow polydopamine nanoparticles, followed by surface conjugation with anti-PSMA nanobodies (VHH) to yield M/B@PDA‑VHH NPs. VHH-mediated recognition confers active targeting toward PSMA-positive PCa cells. Under near-infrared irradiation, the nanoparticles show high photothermal conversion and trigger on-demand release of NO and ML216. NO generation propels nanomotor movement, markedly improving transport across endothelial barriers, penetration into 3D tumor spheroids, and distribution in PCa tissues in vivo. Photothermal/NO treatment induces DNA damage and promote apoptosis. Released ML216 inhibits BLM helicase, leading to replication fork stalling and accumulation of double-strand breaks, and concomitantly suppresses AKT/mTOR signaling via dephosphorylation of p‑AKT and p‑PRAS40. These effects disrupt DNA repair and amplify oxidative damage, restoring therapeutic sensitivity. In vitro and in vivo studies show strong tumor growth inhibition with minimal systemic toxicity. This gas-propelled platform offers a strategy to overcome stromal barriers and resistance in solid PCa.