Advanced azelaic acid hyalubilosome-loaded microneedles for potent anti-inflammatory, antioxidant, and antimicrobial for Acne treatment by up-regulation of Nrf2/HO-1 signaling pathway

Acne vulgaris is a multifactorial inflammatory skin disorder in which the clinical utility of azelaic acid (AZA) is limited by poor aqueous solubility and inadequate skin permeation. This study developed AZA-loaded hyalubilosomes (AZA-HBs) integrated into dissolving PVA/PVP-chitosan microneedles (MNs) to improve dermal delivery and anti-acne efficacy. AZA-HBs formulations were developed using Design-Expert® software to study the effects of hyaluronic acid and bile salt amount, optimized via I-optimal design, and incorporated into dissolving MNs. The optimized AZA-HBs showed high entrapment efficiency (87.0 ± 0.55%), nanosized vesicles (170 ± 0.72 nm), narrow dispersity (PDI 0.33 ± 0.01), and good colloidal stability (zeta potential −29 ± 0.28 mV). The selected MN formulation exhibited excellent drug loading (95.3 ± 1.2%), strong mechanical performance with only (11.0 ± 1.0%) height reduction, and efficient insertion. The hybrid platform provided sustained AZA release, reaching (94–95%) over 48 h, and increased ex vivo skin permeation by (6.3-fold). It also improved cytocompatibility in HaCaT cells, whereas free AZA caused complete cell loss at the highest tested concentration. Moreover, the formulation enhanced antimicrobial potency (MICs of 6.25 μg/mL against S. epidermidis and 12.5 μg/mL against S. aureus ) and eradicated (78%) of the biofilm. In vivo, AZA-HBs/MNs produced the strongest anti-acne effect, markedly reducing ear inflammation, suppressing TNF-α, IL-1β, IL-6, and TLR4, modulating Nrf2/HO-1/MYD88 signaling, and restoring normal histological and EGF immunohistochemical features. AZA-HBs-loaded dissolving PVA/PVP-chitosan microneedles offer sustained release, superior penetration, strong antimicrobial/antibiofilm activity, and significant anti-acne efficacy for topical AZA delivery.