Photoacoustic-imaging nanomotors enhance tumor penetration and alleviate hypoxia for photodynamic therapy of breast cancer

Breast cancer is the most prevalent malignancy worldwide, yet conventional therapies are invasive and prone to resistance, recurrence, and metastasis. Photodynamic therapy (PDT) is a promising noninvasive modality, but its efficacy is limited by tumor hypoxia and poor photosensitizer delivery. Here, we report a photoacoustic-imaging nanomotor, PPIC, which addresses these challenges through integrated functions of oxygen production, deep tissue penetration and photoacoustic imaging. The PPIC nanomotor is constructed by covalently anchoring indocyanine green (ICG) and chlorin e6 (Ce6) on Janus mesoporous Pt-organosilica (JMPO) nanoparticles. The Pt of PPIC catalyzes the decomposition of tumor hydrogen peroxide (H₂O₂) to generate oxygen, which replenishes oxygen for PDT and propels the nanomotor to penetrate deeper into the tumor. PPIC produces reactive oxygen species (ROS) to induce tumor cell apoptosis under 660 nm laser irradiation. This integrated design overcomes tumor hypoxia and enhances photosensitizer delivery, enabling effective PDT. In a 4T1 breast cancer model, PA imaging showed the distribution of PPIC in tumors, accompanied by a significant increase in hemoglobin oxygenation signals, indicating effective <i>in situ</i> oxygen generation. PPIC-mediated PDT reduced the hypoxic marker hypoxia-inducible factor-1 (HIF-1α) expression and achieved complete tumor regression in 4 out of 6 (66.7%) treated mice. <i>In vitro</i> and <i>in vivo</i> safety evaluations demonstrated negligible systemic toxicity. These results indicated that PPIC-mediated PDT can overcome tumor hypoxia and significantly improve therapeutic outcomes, providing a promising strategy for effective cancer phototherapy.