Hyaluronic acid-silybin conjugate for the preparation of multifunctional, biomimetic, vancomycin-loaded self-assembled polymersomes against bacterial sepsis.

Sepsis, a life-threatening disruption, remains a significant global healthcare challenge that urgently needs novel strategies to improve management. This study aimed to develop multifunctional vancomycin-loaded polymersomes (VCM-HA-SIL-Ps) using a novel hyaluronic acid-silybin (HA-SIL) conjugate to target the TLR inflammatory pathway and enhance VCM's efficacy against bacterial sepsis. HA-SIL was synthesized and characterized by FT-IR, UV-Vis spectroscopy, and 1H NMR. The biomimetic properties of HA-SIL were confirmed via in silico (-73.35 kcal/mol) and in vitro (dissociation constant = 2.872 μM) binding affinity studies against TLR2. VCM-HA-SIL-Ps exhibited appropriate physicochemical properties, biocompatibility, and stability. VCM-HA-SIL-Ps sustained VCM release for 48 h, achieving 73.38 % cumulative release. In vitro antibacterial studies showed that VCM-HA-SIL-Ps had superior minimum inhibitory concentration against sensitive and resistant Staphylococcus aureus and faster bacterial killing, compared to free VCM. Additionally, VCM-HA-SIL-Ps demonstrated excellent DPPH radicals scavenging and effective anti-inflammatory activity on bacterial toxin-stimulated cells. Finally, in a mouse model of MRSA-induced sepsis, VCM-HA-SIL-Ps achieved 100 % bacterial eradication, significantly reduced pro-inflammatory markers (IL-6, TNF-α, IL-1β by 2.9-, 1.8-, and 5-fold, respectively), and minimized organ damage. Collectively, these findings demonstrate the potential of HA-SIL as a novel multifunctional adjuvant for effective antibiotic delivery against bacterial sepsis.