Breaking Biofilm Barriers: Using CATH-ICG-Loaded Bilayer Dissolving Microneedle-Assisted Photodynamic Therapy for Deep Skin Candidiasis.

Deep skin fungal infections, particularly biofilm-associated(), pose significant clinical challenges due to their resistance to conventional antifungal therapies. The stratum corneum acts as a barrier to high molecular weight drugs, limiting the penetration of systemic and topical antifungal agents. In this study, we explored a transdermal delivery system utilizing novel Cathelicidin─HcCATH-KL30 (CATH)-loaded dissolving microneedles (DMNs) for the treatment of deep dermalbiofilm infections. Preliminary evaluations demonstrated that CATH exhibited potent antifungal activity against nonfilamentous and filamentousbut was ineffective against biofilm-embedded Candida, suggesting biofilm penetration limitations. To enhance its efficacy, we integrated indocyanine green into DMNs and applied photodynamic therapy (PDT) using near-infrared (NIR) irradiation. The generated reactive oxygen species disrupted the biofilm matrix, allowing a deeper penetration of CATH for enhanced antifungal activity. Results from in vitro, ex vivo, and in vivo models demonstrated a significant reduction (∼94%) in fungal burden with CATH-ICG-DMNs following NIR irradiation, highlighting a synergistic effect. Findings of the study were mechanistically validated through qRT-PCR and propodeum iodide staining, which were in accordance with the proposed hypothesis. The current research work for the first time explored the novel antimicrobial peptide from a drug delivery platform in order to investigate its potential. This study establishes a promising microneedle-based PDT strategy for combating deep skin fungal infections, overcoming biofilm-mediated resistance and enhancing antifungal therapy efficacy.