Supramolecular Assembly‐Enabled Transdermal Therapy of Hypertrophic Scarring Through Concurrent Ferroptosis‐Apoptosis

Abstract Hypertrophic scar (HS) remains a major challenge for clinicians due to unsatisfactory therapeutic performance. Although inducing apoptosis of HS fibroblasts (HSFs) has proved to be an effective nonsurgical treatment strategy, potential chemotherapy resistance to apoptosis of HSFs makes the development of new and efficient strategies highly demanding. Herein, a ferroptosis‐apoptosis combined therapeutic strategy for the treatment of HS is developed through supramolecular self‐assembly between cucurbit[7]uril (CB[7]) and two bioactive agents, dihydroartemisinin (DHA) and gold nanoclusters (AuNCs). The resulting self‐assembled supramolecular nanoparticles, named CAD NPs, showed high guest loading efficiency and prominent pH‐responsive degradability in the acidic lysosomes of HSFs. Importantly, both DHA and AuNCs act synergistically to generate excessive reactive oxygen species and lipid peroxidation, leading to mitochondrial damage, and ultimately inducing concurrent ferroptosis and apoptosis on HSFs. Upon further loading into hydrogel microneedles to facilitate their transdermal delivery, these CAD NPs showed superior antiscar therapeutic effects in shortening the treatment span to 3 weeks and improving the HS appearance, as demonstrated at a rabbit ear model of HS. The present supramolecular assembly‐based ferroptosis‐apoptosis strategy provides an innovative guideline for efficiently treating HS as well as other diseases.