Designing HA–PVA composite microneedles with synergistic mechanical reinforcement for deep skin MRSA biofilms: unveiling a new antimicrobial target

Deep skin MRSA biofilm infections are difficult to treat because the effective delivery of antimicrobial concentrations at deep skin is challenging. HcCATH-KL30 (CATH) – a novel Cathelicidin peptide isolated from sea snake have shown potential antimicrobial activity. However, hydrophilicity and high molecular weight (∼3.4 kDa) limit its permeation across skin making it unsuitable for conventional topical delivery. To overcome these problems, bilayer CATH dissolving microneedles (CATH-DMNs) were prepared from a mechanically reinforced composite matrix system of hyaluronic acid–polyvinyl alcohol (HA–PVA). The prepared microneedle system was characterized for morphology, mechanical properties, insertion studies, skin distribution, in-vitro, ex-vivo, in-vivo, mechanism and safety studies. The optimized architecture showed strong mechanical strength (28.6 ± 0.7 N/patch), high CATH loading (113 ± 10 μg/patch), and deep skin penetration (∼530 μm). DMNs dissolved in 45 min, while cytotoxicity at 200 μg/mL remained <20%. In vitro and ex vivo findings showed ∼99% reduction in MRSA burden, while in vivo efficacy was interesting and significantly eradicated the bacterial burden within 4 days. Faster effect than conventional antibiotics highlighting the potent nature of CATH. Mechanistic insights showed membrane disruption by CATH followed by AgrA suppression directly, unveiling a new antimicrobial target by Cathelicidin family of peptides