Destroy and reconstruct: A microneedle platform for combined NIR-II photothermal therapy and asiaticoside-mediated tissue regeneration in cutaneous amyloidosis.

Cutaneous amyloidosis (CA) is a chronic skin disorder characterized by dermal amyloid deposition, accompanied by fibroblast hyperproliferation and keratinocyte apoptosis, yet current treatments are limited by poor transdermal delivery and inadequate lesion clearance. Here, we present a "destroy-reconstruct" strategy using dissolving microneedles (MNs) co-loaded with asiaticoside (AS) and a NIR-II photothermal agent (IR1048), modified with octaarginine (R8) for enhanced cellular uptake. The optimized AI-MN@R8 platform exhibited excellent mechanical strength, rapid in vivo dissolution within 20 min, and a photothermal conversion efficiency of 33.58% under 1064 nm laser irradiation. In vitro studies demonstrated that R8 modification significantly enhanced cellular uptake, and the combination of photothermal therapy and AS synergistically suppressed human skin fibroblasts (HSF) proliferation and migration via inhibition of the EGFR/PI3K/AKT pathway. In a rat model of localized CA, AI-MN@R8 combined with laser irradiation achieved targeted dermal delivery, real-time temperature elevation to approximately 47, and near-complete amyloid clearance, as confirmed by Congo red and Thioflavin 488 staining. Histological and immunohistochemical analyses further revealed restored dermal architecture, reduced collagen deposition, and normalized epidermal keratin expression (KRT5/KRT14). Mechanistically, Western blot analysis of skin tissues confirmed that AI-MN@R8 treatment regulated the Bax/Bcl-2 ratio, inhibited Caspase-3 activation, and downregulated fibrosis-related proteins (COL1A1/COL3A1), reversing the fibrotic microenvironment. No systemic toxicity was observed in major organs. This synergistic photothermal-pharmacological platform offers a safe and effective strategy for CA treatment with high clinical translational potential.