Fluorinated polymeric nanoplatform relieves tumor hypoxia and enhances chemo-sonodynamic therapy

Hypoxia is a hallmark of the solid tumor microenvironment and a key factor limiting therapeutic efficacy in osteosarcoma (OS), as it can promote chemoresistance and impair reactive oxygen species generation during sonodynamic therapy (SDT). Current strategies to alleviate tumor hypoxia, however, remain limited by insufficient endogenous oxygen production and inefficient exogenous oxygen delivery. To address this, we developed a tumor-targeted polymeric nanoplatform designed to relieve hypoxia. An oxygen-delivery system, named PPFCD, was constructed using a fluorine-rich block as an oxygen reservoir and phenylboronic acid side chains for efficient co-loading of doxorubicin (DOX) and chlorin e6 (Ce6). The oxygen carried by the fluorinated segments effectively mitigated intratumoral hypoxia. Upon ultrasound irradiation, PPFCD exhibited a strong sonodynamic effect, which, combined with the high DOX load, led to synergistic chemo-sonodynamic antitumor activity. In an orthotopic OS mouse model, this nanoplatform increased oxygen saturation by ∼10%, inhibited tumor growth by ∼90%, and triggered robust innate and adaptive immune responses. In summary, this study presents a polymeric nanoplatform capable of tumor-specific co-delivery of oxygen and drugs, offering important insights into overcoming the challenges of SDT for solid tumors. STATEMENT OF SIGNIFICANCE: Polymeric Drug Delivery System: A polymeric carrier is employed to co-load an antitumor agent (doxorubicin, DOX), a sonosensitizer (chlorin e6, Ce6), and oxygen, enabling the simultaneous delivery of multiple therapeutic components. Multi-Action Anti-Tumor Platform: The platform incorporates pendant phenylboronic acid (PBA) that enables nitrogen-boron coordination with DOX and hydrophobic interactions with Ce6, together with a fluorine-containing block with high oxygen affinity. Highly Effective Antitumor Activity: The platform elicits strong innate and adaptive immune responses and markedly inhibits osteosarcoma progression, with tumor volumes reduced to approximately 20% of those in the control group. Clinical Application Potential: This platform features a simple formulation, with key components including DOX, Ce6, and polyethylene glycol (PEG), all of which have been approved by the FDA. It demonstrates substantial therapeutic potential in osteosarcoma and shows promising prospects for future clinical translation.