In situ microneedle-based system with “Tripartite Delivery” characteristics for local antisense oligonucleotide therapy in acute bacterial infections

Abstract

The management of the acute bacterial infections in the traumatic skin remains a significant challenge in clinical. The application of antibiotics on wounds is typically avoided due to antimicrobial resistance risks. Antisense therapeutics, like antisense oligonucleotides (ASOs), present a selective, low-resistance alternative, but effective bacterial uptake is still a major obstacle. In this work, we developed a novel microneedle-based delivery system (MNDS) distinguished by its distinctive multifunctional hydrogels and a “Tripartite Delivery” mechanism. The MNDS was designed with a bionic mushroom-shaped multilayered structure. Upon application, the MNDS enabled an initial rapid release and sustained release of the encapsulated nanocomplexes (ASO@GP-SiNPs). The needle body layer hydrogels can respond to hyaluronidase and continuously release hyaluronic acid and ε-polylysine for several days. These ASO@GP-SiNPs were effectively uptaken by E. coli (46.4 %) and S. aureus (37.1 %), subsequently releasing ASOs that target the acpP and ftsZ genes to effectively eliminate bacteria. The system exhibits significant antibacterial activity and effectively inhibits biofilm formation, while also inducing the polarization of macrophages toward an M2-like phenotype. Additionally, the system demonstrates excellent biocompatibility. In conclusion, this paper presents a novel strategy for addressing the challenges of acute bacterial infections in traumatic skin by utilizing the advanced functionalities of MNDS.