Rapamycin as a “One-Stone-Three-Birds” Agent for Cooperatively Enhanced Phototherapies Against Metastatic Breast Cancer

Cooperative photothermal therapy (PTT) and photodynamic therapy (PDT) represents a promising strategy to conquer tumor with synergistic effect, while their long-term efficacy has been strictly limited by the multiple resistances of tumor. Here, we reported a core–shell nanoplatform for enhanced PTT/PDT combination against metastatic breast cancer. The nanosystem had photosensitizer chlorin e6 (Ce6) and rapamycin (RAP) pure drugs core and the polydopamine (PDA) shell, with surface PEGylation. Notably, we found that RAP was a highly robust sensitizer to boost the efficacy of both PTT and PDT by inhibiting the expression of heat shock protein 70 (HSP 70) and hypoxia inducible factor-1α (HIF-1α), respectively, resulting in cooperatively enhanced antitumor efficiency. Moreover, metastasis, the fatal risk of breast cancer, was also inhibited by virtue of RAP-mediated matrix metalloproteinases-2 (MMP-2) suppression. Upon intravenous injection, the nanosystem could passively accumulate into the tumor and impose potent phototherapies upon dual laser irradiations for complete tumor elimination and metastasis inhibition, giving rise to 100% mice survival over a long observation period. Collectively, this work offers a general solution to address the key limitations of tumor-resistant phototherapies and provides a highly promising nanoplatform for the management of metastatic cancer.