Oxygen-Self-Supplying and HIF-1α-Inhibiting Core-Shell Nanosystem for Hypoxia-Resistant Photodynamic Therapy

Extreme hypoxia together with the expression of hypoxia-inducible factor-1α (HIF-1α) represents a significant barrier against the effective photodynamic therapy (PDT) of tumor. To mitigate these issues, we created a core-shell nanosystem that can simultaneously alleviate tumor hypoxia and suppress the expression of HIF-1α to combat tumor resistance against PDT. Specifically, a carrier-free, dual-drug nanocore was formed by the self-assembly of hydrophobic photosensitizer (chlorin e6, Ce6) and rapamycin (RAP), and then the surface was coated by a layer of metal-organic frameworks (MOFs) to load catalase, reaching an overall drug loading of ∼60%. In such system, catalase acted as oxygen-self-supplier to catalyze the decomposition of tumor-abundant H₂O₂ into O₂, and the sustained release of RAP downregulated HIF-1α, which collectively potentiated the PDT efficacy against tumor. The nanosystem could passively accumulate into tumor, realize in situ oxygen generation and HIF-1α inhibition in tumor tissue, and thus exhibit strong PDT effect toward highly hypoxia tumor. This work provides a highly promising nanoplatform to reverse hypoxia-mediated tumor resistance and overcome the restriction of PDT treatment.