Oleanolic Acid-Loaded Organosilica Nanoparticles for Synergistic Anti-Inflammatory and Antibacterial Therapy via Inducing Macrophage Polarization

Abstract Chronic inflammatory diseases caused by bacterial infections are notoriously difficult to treat due to the formation of a vicious cycle in which bacterial infection and immune dysregulation mutually reinforce each other at the lesion site. Current antibiotic therapies face the dual challenges of escalating drug resistance and insufficient immunomodulatory capacity. Inspired by stimuli-responsive nanodrug delivery systems, we herein constructed a glutathione-responsive dendritic mesoporous organosilica nanoparticles (DMOS NPs) loaded with oleanolic acid (OA), namely DMOS@OA NPs, aiming to achieve synergistic antibacterial and anti-inflammatory therapy. The DMOS@OA NPs exhibited a uniform hydrodynamic diameter of approximately 232.1 ± 9.49 nm with typical dendritic spherical morphology, a drug loading capacity of 30.01%, and an encapsulation efficiency of 85.74%. In vitro release experiments demonstrated that DMOS@OA NPs displayed significant pH-responsive release behavior, achieving a cumulative OA release of 58.98% under acidic conditions (pH 5.5). Furthermore, the DMOS@OA NPs could respond to high concentrations of glutathione by cleaving tetrasulfide bonds to release therapeutic hydrogen sulfide (H2S). Antibacterial assays revealed that DMOS@OA NPs exhibited remarkable bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA), with superior efficacy compared to DMOS NPs and OA, and effectively inhibited bacterial biofilm formation with an inhibition rate of 85.78%. Scanning electron microscopy observations further confirmed that the DMOS@OA NPs could disrupt bacterial membrane integrity, leading to bacterial lysis and death. In vitro anti-inflammatory experiments demonstrated that DMOS@OA NPs possessed good biocompatibility and could significantly downregulate the expression of the M1 macrophage marker CD86 while upregulating the M2 marker CD206, and reduced the secretion of pro-inflammatory cytokines IL-1β and TNF-α, effectively inducing macrophage polarization from the pro-inflammatory phenotype to the anti-inflammatory phenotype. In conclusion, we successfully constructed a GSH-responsive DMOS@OA nanosystem with dual antibacterial and anti-inflammatory functions. Through the synergistic action of H2S and OA, this nanosystem achieves integrated efficient bactericidal activity and immunomicroenvironment regulation, providing a highly promising novel nanotherapeutic strategy for the treatment of chronic infectious inflammatory diseases.