Fully armed photodynamic therapy with spear and shear for topical deep hypertrophic scar treatment

5-aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT) has emerged as a promising therapy for hypertrophic scar (HS). However, the poor permeability of ALA across biological barriers and pro-survival autophagy of fibroblasts largely restricted the efficacy of PDT. Herein, PDT was well equipped with spear and shear to overcome the therapeutic resistance. Specifically, hyaluronidase (HAase) based dissolving microneedles (MN)with improved stiffness and permeability were developed as a spear to deliver ALA into deep lesions by combating the dual barriers of stratum corneum and dense extracellular matrix (ECM). Besides, metformin (Met) MN was applied as a shear to intervene the respiration and autophagic process for amplified PDT. HAase significantly enhanced the in vitro and in vivo transdermal delivery efficiency of ALA, while the combination of HAase and Met successfully amplified the anti-scarring efficacy of PDT by elevating cytotoxicity, promoting permeation, activating signal pathways, and interdicting the autophagy process simultaneously. The pharmacodynamics study revealed that the combination therapy achieved the lowest scar elevation index (SEI), downregulated expression of collagen I and TGF-β1, and decreased LC3 II/I ratio, showing excellent therapeutic efficacy. Therefore, such a fully armed PDT integrating double-prolonged attack on the physiological and pathological barriers offers a promising topical treatment for deep HS.