Non‐Invasive Transdermal Delivery Systems with Deep Tissue Penetrating Ability for Local ROS‐Modulating Chemotherapy

Cutaneous melanoma is the deadliest malignant skin cancer due to its poor prognosis, rapid local growth, and high metastasis. Transdermal administration for local drug delivery would be one of the most appropriate therapy regimens. However, promoting drug penetration into deep tumor tissue and maintaining the balance of redox homeostasis during the antitumor treatment to inhibit melanoma progression remains a great challenge in melanoma treatment. Herein, non‐invasive transdermal delivery systems are reported for melanoma treatment, which is composed of biocompatible hydrogel and penetrating nanocarriers. Highly penetrating nanocarriers can co‐deliver paclitaxel and coenzyme Q10 for inhibiting melanoma and reducing side effects, which are attributed to drug encapsulation, deep tissue penetration, high cellular uptake, and organelle targeting. More importantly, biocompatible hydrogels serve as nanocarriers platforms for melanoma location and transdermal delivery. This hierarchical nanoparticle‐hydrogel system achieves high‐efficiency non‐invasive transdermal delivery for inhibiting melanoma, blocking adverse effects, and restraining melanoma development. Incorporating antioxidants into antitumor treatment can reduce reactive oxygen species (ROS) levels in the tumor microenvironment, withstand external stimuli such as UV–irradiation and chemotherapy, and prevent side effects and melanoma development. Engineering non‐invasive penetrating delivery systems facilitate bioactive molecules to combat sequential physio‐pathological barriers including multiple skin barriers (corneum and epidermal layer), tumor microenvironment, cellular and subcellular barriers for local ROS‐modulating chemotherapy.