A tunable nanocomposite hydrogel based on carboxymethyl chitosan/chitooligosaccharide for on-demand tissue-targeted drug delivery in psoriasis treatment.

While the enhanced permeability of psoriatic skin facilitates topical delivery, it also poses challenges in drug retention and systemic absorption. To address these limitations, we designed a tunable nanocomposite hydrogel composed of poly(lactic acid)-hyperbranched polyglycerol-based bioadhesive nanoparticles (BNPs), carboxymethyl chitosan (CMCS), and chitooligosaccharide (COS), which enables on-demand drug delivery with deep epidermal retention and sustained release. The hydrogel's degradation rate is controlled by component ratios, permitting tunable degradation and sustained nanoparticle release for up to 7 days. During degradation, it gradually releases entrapped water and non-adhesive BNP/COS. The released water increases skin hydration from 9 % to 20 %, promoting deeper nanoparticle penetration. Once inside, COS diffuses away, while BNPs adhere to deep epidermal layers, thereby ensuring site-specific and sustained celastrol (Cel) release via a degradation-penetration-adhesion mechanism. The system achieved ~80 % cumulative Cel release over 4 days in vitro and demonstrated prolonged retention in psoriatic lesions, with >75 % of BNPs remaining after 1 day and persisting for over 4 days. In addition, the synergistic anti-inflammatory effects of Cel and COS further enhanced therapeutic efficacy. A single dose of Cel/BNP/CMCS/COS hydrogel reduced the Psoriasis Area and Severity Index (PASI) and skin thickness by over 60 % within 3 days in the imiquimod-induced psoriasis model.