摘要Photodynamic therapy(PDT)-mediated oxidation treatment is extremely attractive for skin melanoma ablation,but the strong hydrophobicity and poor tumor selectivity of photosensitizers,as well as the oxygen-consuming properties of PDT,leading to unsatisfactory therapeutic outcomes.Herein,a tumor acidic microenvironment activatable dissolving microneedle(DHA@HPFe-MN)was developed to realize controlled drug release and excellent chemo-photodynamic therapy of melanoma via oxidative stress amplification.The versatile DHA@HPFe-MN was fabricated by crosslinking a self-synthesized protoporphyrin(PpIX)-ADH-hyaluronic acid(HA)conjugate HA-ADH-PpIX with"iron reservoir"PA-Fe3+complex in the needle tip via acylhydrazone bond formation,and dihydroartemisinin(DHA)was concurrently loaded in the hydrogel network.HA-ADH-PpIX with improved water solubility averted undesired aggregation of PpIX to ensure enhanced PDT effect.DHA@HPFe-MN with sharp needle tip,efficient drug loading and excellent mechanical strength could efficiently inserted into skin and reach the melanoma sites,where the acidic pH triggered the degradation of microneedles,enabling Fe-activated and DHA-mediated oxidation treatment,as evidenced by abundant reactive oxygen species(ROS)generation.Moreover,under light irradiation,a combined chemo-photodynamic therapeutic effect was achieved with amplified ROS generation.Importantly,the Fe-catalyzed ROS production of DHA was oxygen-independent,which work in synergy with the oxygen-dependent PDT to effectively destroy tumor cells.This versatile microneedles with excellent biosafety and biodegradability can be customized as a promising localized drug delivery system for combined chemo-photodvnamic therapy of melanoma.