Hierarchical Nanoarchitectonics of Hyaluronidase-Powered and Chitosan-Interfaced Liposomal Microneedles for Chemotherapeutic Extravasation Treatment

Chemotherapeutic drug extravasation causes severe local inflammation and tissue necrosis. Conventional dexamethasone (DEX) therapies for extravasation anti-inflammation are limited by poor skin penetration, short local retention, and resultant subpar therapeutic effects. To address these challenges, a transdermal microneedle (MN) platform was engineered via hyaluronidase- and chitosan-modified liposomal DEX nanoarchitectonics (H+CS-LDEX-MNs), forming a synergistic cascade to achieve efficient drug transport and residence at the lesion site. The electrostatic adsorption of CS onto LDEX yielded a stable, positively charged nanosystem (231.53 ± 1.47 nm, + 47.73 ± 1.15 mV), achieving a 2.7-fold increase in site-specific retention compared with unmodified LDEX-MNs ( p < 0.001). HAase-mediated extracellular matrix remodeling further enhanced permeation, with cumulative drug delivery reaching 13.5 μg/cm 2 at 24 h, representing a 23% improvement over LDEX-MNs in ex vivo porcine skin. In the paclitaxel extravasation mouse model, the therapeutic H+CS-LDEX-MNs group achieved nearly complete ulcer closure by day 5 (ulcer area <10 mm 2 ), whereas prophylactic administration maintained ulcer areas close to 0 mm 2 throughout 20 days. Moreover, H+CS-LDEX-MNs significantly attenuated inflammatory cytokine expression, reducing TNF-α levels by over 70% relative to the saline-treated group ( p < 0.001). Collectively, this hierarchical nanoarchitectonics design confers enhanced skin penetration, prolonged drug retention, and robust anti-inflammatory efficacy, underscoring the strong translational potential of this multifunctional microneedle system for the prevention and treatment of chemotherapy-induced skin injury.