Versatile Targeted Celastrol Nanoassemblies for Enhanced Immunomodulatory Effects Against MRSA Infection

The escalating crisis of antimicrobial resistance, driven by pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), underscores the urgent demand for innovative therapeutic strategies that outperform conventional antibiotic regimens. In this study, we developed a versatile targeted celastrol nanoassembly (CDPG) that integrates site-specific antibacterial delivery with coordinated immunomodulation to effectively address MRSA infections and prevent their recurrence. The nanoassembly consists of a celastrol-dextran antibacterial core encapsulated by a polyethylene glycol (PEG) shell, which is linked via pH-sensitive boronate ester bonds and stabilized through the reconstitution of the β-glucan triple-helix structure. This design enables prolonged systemic circulation under physiological conditions. Upon reaching the acidic microenvironment of the bacterial infection site, the nanoassembly undergoes PEG layer dissociation, exposing dextran moieties that enhance pathogen targeting through lectin-mediated recognition, while simultaneously releasing β-glucan to activate both innate and adaptive immune responses. In murine models of MRSA infection, CDPG demonstrated precise accumulation at lesion sites, potent bactericidal efficacy, modulation of inflammatory responses, and induction of systemic immune activation upon rechallenge. This study presents a natural product-derived, rationally designed nanomedicine strategy that integrates stimulus-responsive structural transformation, pathogen-targeted drug delivery, and modulation of the host immune system, offering a hopeful therapeutic approach to combat multidrug-resistant bacterial infections.