Mitigating Lactate-Associated Immunosuppression against Intracellular Bacteria Using Thermoresponsive Nanoparticles for Septic Arthritis Therapy

Intracellular bacteria are the major contributor to the intractability of septic arthritis, which are sequestered in macrophages to undermine the innate immune response and avoid the antibacterial effect of antibiotics due to the obstruction of the cell membrane. Herein, we report a thermoresponsive nanoparticle, which consists of a phase-change material shell (fatty acids) and an oxygen-producing core (CaO₂-vancomycin). Under external thermal stimulation, the shell of the nanoparticle transforms from a solid phase to a liquid phase. Then the CaO₂-Vancomycin core is exposed to the surrounding aqueous solution to release vancomycin and generate Ca(OH)₂ and oxygen, thereby depleting accumulated lactate to mitigate lactate-associated immunosuppression, stabilizing hypoxia-inducible factor-1α (HIF-1α) to enhance M1-like polarization of macrophages, and increasing reactive oxygen species (ROS) and reactive nitrogen species (RNS) production. This combined effect between the controlled release of antibiotics and enhancement of host innate immunity provides a promising strategy to combat intracellular bacteria for septic arthritis therapy.