Dissolvable silk microneedles delivering minocycline-loaded ZIF-8 nanoparticles for targeted modulation of sebocyte metabolism and improved acne therapy.

BACKGROUND: Acne Vulgaris (AV) lesions exhibit an acidic, sebum-rich, and inflammation-prone microenvironment in which conventional minocycline therapy is constrained by the stratum-corneum barrier and systemic exposure. Here, we present the fabrication and application of dissolvable silk fibroin microneedles encapsulating minocycline-loaded zeolitic imidazolate frameworks (Mino@ZIF-8/SF MNs) to achieve sebaceous gland-targeted, pH-responsive delivery and multimodal therapy.

RESULTS: The Mino@ZIF-8/SF MNs display uniform conical morphology, excellent mechanical robustness (peak failure force ≈ 0.4 N per needle), rapid dissolution (< 1 min), high drug loading (≈ 40.11%) and encapsulation efficiency (≈ 70.2%), and negligible hemolytic activity. Under mildly acidic conditions (pH 5.5), minocycline release was markedly accelerated compared to physiological pH 7.4, reflecting the acidified acne microenvironment. Functionally, Mino@ZIF-8/SF MNs achieved > 95% inhibition of Cutibacterium acnes at 30 µg/patch and substantially attenuated sebocyte inflammatory responses. In heat-killed C. acnes-stimulated SZ95 sebocytes, the Mino@ZIF-8/SF MNs downregulated NFKB1, IL-1α, IL-1β, IL-6, IL-8 and MMP9 expression, along with suppression of cytokine-cytokine receptor interaction, IL-17 and NET-associated signaling pathways. RNA-sequencing also suggested that sebocyte metabolism may undergo reprogramming involving enhanced apoptosis, maintenance of mitochondrial oxidative activity, and modulation of PPARγ-related lipid metabolism, which could collectively contribute to reduced lipid droplet accumulation. In a C. acnes-induced acne-like mouse model, Mino@ZIF-8/SF MNs markedly accelerated lesion resolution, reduced lesion elevation, eschar formation, and diameter scores, normalized epidermal thickness, and decreased sebaceous lipid accumulation, while exhibiting no detectable systemic toxicity as confirmed by histology, hematology, and serum biochemistry.

CONCLUSION: Collectively, this study establishes a nanobiotechnology platform that integrates metal-organic frameworks(MOF)-based pH-responsive delivery with antibacterial, anti-inflammatory, and metabolic reprogramming activities, offering a precise and minimally invasive multimodal strategy for sebaceous gland-targeted acne therapy.