Ultrasound-activated and P-selectin-targeted liposomes overcome biofilm barriers for surgical site infections therapy.

Pseudomonas aeruginosa-induced biofilm-associated surgical site infections (BSSIs) pose a dual therapeutic challenge: the dense extracellular polymeric substances (EPS) barriers hinder drug enrichment and penetration, whereas the immunosuppressive microenvironment within the biofilm impedes infection clearance, leading to persistent bacterial colonization and recurrence. This study developed an ultrasound-activated P-selectin-targeted liposome (SPCMPL) integrating natural sulfatide ligands (targeting P-selectin overexpressed in inflamed BSSI vasculature), sonosensitizer chlorin e6 (Ce6), meropenem prodrug, and perfluoropentane (PFP) to achieve efficient antibiotic delivery and BSSI treatment via breaking through the biofilm barriers and activating immunomodulation. SPCMPL employed ligand/receptor-mediated transcytosis for enrichment in BSSI lesions, where the PFP phase transition triggered by ultrasound disrupted the biofilm EPS structure. This process can both trigger the in-situ generation of reactive oxygen species (ROS) by Ce6 and loosen the EPS matrix. This degradation then facilitated meropenem release, allowing it to penetrate the biofilm more effectively and achieve antimicrobial concentrations throughout. Furthermore, the mass-produced ROS polarized macrophages to a pro-inflammatory M1 phenotype, thereby enhancing phagocytosis, remodeling the microenvironment, and inhibiting biofilm persistence. Ultrasound-triggered spatial control localized antibiotic release and immunomodulation to the infection site, optimizing local delivery while minimizing systemic toxicity and reducing the risk of systemic cytokine storms. The results demonstrated that the SPCMPL with ultrasound manipulation integrated biofilm disruption, targeted drug release, and immunomodulation to completely eradicate both planktonic and biofilm-embedded bacteria and effectively treat BSSI.