Chun_2025_Int.Immunopharmacol_165_115499

Bacterial infections frequently trigger severe inflammatory cascades accompanied by oxidative stress responses, which collectively impair tissue regeneration and exacerbate disease progression. Consequently, there is a pressing clinical need to develop therapeutic strategies capable of simultaneously eradicating pathogenic bacteria and modulating the infection microenvironment. The infected tissue microenvironment is characterized by macrophage infiltration and upregulation of folate receptor expression on their cellular surfaces. Concurrently, pathogenic bacteria actively secrete abundant lipase at the site of infection. In this study, we developed an infection-targeting nano-micelle system with lipase-responsive drug release capabilities (FA/AC-M)which were self-assembled from TPGS and DSPE-PEG(2000), with folic acid (FA) modification on the surface. The ester group in DSPE-PEG(2000) was sensitive to lipase. FA/AC-M was found to possess uniform size, smooth morphology, satisfactory stability and encapsulation efficiency. The encapsulated Ampicillin and Curcumin exhibited synergistic antibacterial effect evidenced by Synergy Finder analysis. In vitro, FA/AC-M could effectively change bacterial membrane permeability, result in protein leakage, inactivate planktonic bacteria, inhibit biofilm formation and reduce intracellular bacterial burden. Additionally, FA/AC-M selectively targeted inflamed RAW 264.7 cells and bacterial infection sites, demonstrated by in vivo and in vitro studies. Besides, the incorporation of Cur into FA/AC-M achieved significant enhancement of immunomodulatory activity and antioxidant capacity. In vivo evaluation using a methicillin-resistant Staphylococcus aureus (MRSA)-infected murine thigh muscle model demonstrated that:FA/AC-M remarkably reduced bacterial counts at the infection site, alleviated inflammatory responses, prompted M2 polarization of macrophage. Therefore, FA/AC-M provides a promising therapeutic approach for the treatment of MRSA infections.