Abstract
5-Aminolevulinic acid-based photodynamic therapy (ALA-PDT) has emerged as a promising therapeutic strategy for psoriasis owing to its non-invasiveness and high selectivity. However, clinical translation is hindered by inadequate cutaneous permeability and the paradoxical interplay between pro-apoptotic effect and oxidative stress. Therefore, this study develops biphasic delivery liposome loaded with 5-ALA and ginsenoside Rg3, and designs hydrogel-backed shield microneedles (SMNs) inspired by shield tunneling principles to achieve efficient delivery. Flow cytometry analysis demonstrates that the biphasic delivery liposome harnesses Rg3 to activate the SOD/CAT antioxidant enzyme system, thereby scavenging excess reactive oxygen species (ROS) generated by 5-ALA-PDT. Incorporation of this liposome into shield microneedles disrupts the psoriatic-thickened stratum corneum barrier and enhances its cutaneous permeation. In an imiquimod-induced mouse model of psoriasis, the microneedle system ameliorates skin lesions and restores immune homeostasis by inhibiting STAT3 phosphorylation, modulating splenic Th17 cell differentiation, and down-regulating serum IL-17A levels. Importantly, this regulatory effect on key inflammatory cytokines, including IL-6 and TNF-α, is further validated using an in vitro psoriasis-like cell model. The biphasic delivery liposome-shield microneedle system synergistically enhances photodynamic efficacy through oxidative homeostasis restoration, immune-inflammatory network modulation, and transdermal permeabilization, establishing a novel combinatorial approach for psoriasis management.