Next-Generation Minimally Invasive Anti-Aging Therapy: Incorporation of Resveratrol-Nicotinamide Cerosomes into PLGA Microneedles for Enhanced Skin Permeation

<b>Background/Objectives</b>: Skin aging and wrinkle formation are primarily driven by ultraviolet (UV)-induced oxidative stress and inflammation. Resveratrol (RSV) and nicotinamide (NCT) possess potent anti-aging properties but suffer from poor skin penetration. This study aimed to develop an advanced transdermal delivery system incorporating RSV/NCT-loaded cerosomes within poly(lactic-co-glycolic acid) (PLGA) microneedles to enhance skin permeation and anti-aging performance. <b>Methods</b>: RSV/NCT-loaded cerosomes were formulated using thin-film hydration of phosphatidylcholine, ceramides (III, IIIB, and VI), and poloxamer surfactants, subsequently optimized via a D-optimal mixture design. PLGA microneedles with optimized cerosomes were tested for their mechanical strength, penetration, drug loading, and release. Ex vivo permeation and in vivo evaluations were performed using a UVA-induced skin wrinkling model. <b>Results</b>: Optimized cerosomes exhibited high entrapment efficiency for RSV and NCT (91 ± 0.56% and 85 ± 0.56%, respectively), nanoscale size (195 ± 0.78 nm), low polydispersity (0.23 ± 0.01), and a negative zeta potential (−22 ± 0.45 mV). PLGA microneedles exhibited sufficient mechanical integrity and effective penetrability through Parafilm^® layers. Microneedle-loaded cerosomes enabled sustained drug release (approximately 65–70% over 48 h) and enhanced ex vivo permeation, approximately for NCT and RSV (1450 μg/cm² and 1000 μg/cm², respectively). In vivo investigations revealed improved skin appearance, restoration of epidermal thickness and collagen architecture, reduced levels of inflammatory cytokines (TNF-α, IL-1β, IL-6, NLRP3), reduced oxidative stress biomarkers (GSH, GPx, MDA, SOD), and genetic upregulation of VEGF, TGF-β1, and β-Catenin. <b>Conclusions</b>: The RSV/NCT cerosome-encapsulated PLGA microneedle system offers a promising, minimally invasive approach with superior transdermal delivery, sustained efficacy, and significant anti-aging benefits.