The development of antibiotic resistance and inadequate immune response in chronic inflammation pose significant challenges in treating chronic osteomyelitis. As accepted non-antibiotic antimicrobial therapies, sonodynamic therapy (SDT) and photothermal therapy (PTT) are recognized for their effectiveness in eliminating bacteria and promoting tissue repair, rendering them promising therapeutic strategies for treating bacterial infections and preventing the emergence of drug-resistant bacteria. However, the antimicrobial action and efficacy in promoting tissue repair depend on the activation status of the host immune system. In this study, by encapsulating horseradish peroxidase (HRP)-loaded gold/polydopamine (PDA) nanoparticles within DOTAP/DOPE cationic liposomes (DLPs), a novel multifunctional nanocatalyst, Au/PDA/HRP@DLP (APH@DLP), was developed to achieve antimicrobial effects and immunological reprogramming of chronic osteomyelitis through synergistic SDT and PTT. The impact on immune activation was investigated by assessing the anti-infective and healing effects in osteomyelitis rat models. The release of bacterial-associated antigens during treatment serves as an in situ vaccine, activating antigen-presenting cells and further stimulating adaptive immunity, while also inducing immune memory that significantly reduces the risk of recurrence. Additionally, macrophage phenotypic transformation during SDT and PTT facilitates tissue repair. This study highlights the role of immune activation in SDT/PTT-based antimicrobial therapy and suggests new strategies for treating chronic osteomyelitis.