Fluorinated phosphate-modified micelles for bone-targeted oxygen delivery enabling enhanced photodynamic therapy of osteomyelitis.

Abstract

Osteomyelitis caused by methicillin-resistant Staphylococcus aureus (MRSA) remains one of the most challenging bone infections to treat clinically. Biofilm formation and the typical hypoxic microenvironment of infected bone tissue jointly undermine the efficacy of conventional antibiotic therapy and emerging photodynamic therapy. Although photodynamic therapy (PDT) offers a non-antibiotic approach to kill bacteria by generating reactive oxygen species (ROS), its clinical application is limited by a combination of barriers: poor photosensitizer accumulation at the infection site, insufficient ROS generation under hypoxia, and the inability of most nanocarriers to penetrate the dense biofilm matrix. This article reports the rational design of an amphiphilic fluorinated phosphate molecule, PF-VPA, which self-assembles into stable micelles (PFPMs) in aqueous solution, addressing all three limitations. The perfluorinated carbon hydrophobic core exhibits high oxygen solubility, exhibiting a 158% increase in dissolved oxygen after oxygen saturation, whereas the non-fluorinated counterpart showed a 59% increase, and its uniquely low surface energy facilitates penetration into the biofilm matrix. The phosphate-functionalized hydrophilic shell selectively binds to hydroxyapatite, thereby achieving bone-specific accumulation and prolonging local retention time. When loaded with the photosensitizer chlorin e6 (Ce6) and presaturated with oxygen, the resulting CPFPMs + O₂ exhibits significantly enhanced singlet oxygen (1O2) production under 660 nm laser irradiation, even under hypoxic conditions. In vitro and in vivo studies demonstrate that CPFPMs + O₂ possesses excellent antibacterial and antibiofilm efficacy against MRSA, while also promoting bone deposition and prolonging drug retention time. More importantly, this multifunctional system also promotes bone regeneration in an osteomyelitis model. In summary, this work presents a multifunctional nanoplatform integrating bone targeting, oxygen delivery, and enhanced PDT, offering a promising strategy for treating refractory osteomyelitis and other hypoxia-associated biofilm infections.