Antitumor Cream: Transdermal Hydrogel Containing Liposome‐Encapsulated Ruthenium Complex for Infrared‐Controlled Multimodal Synergistic Therapy

Abstract A transdermal drug delivery cream, which is non‐invasive and painless, containing a liposome‐encapsulated Ru(II) complex ( LipoRu ) is created for the treatment of skin cancer. This formulation capitalizes on the synergistic antitumor effects of two‐photon excited photodynamic therapy (PDT), photothermal therapy (PTT), and chemotherapy. LipoRu exhibits effective tumor accumulation, efficient cellular uptake, pH‐sensitive and infrared‐accelerated release, and dual localization to the nucleus and mitochondria. The released Ru(II) complexes within cells exert multiple antitumor mechanisms, such as DNA topoisomerase and RNA polymerase inhibition, Type I and II PDT, PTT, DNA photodamage, and apoptosis and ferroptosis induction. The biodistribution and therapeutic efficacy of LipoRu in vivo are systematically compared via three distinct administration routes: intratumoral injection, intravenous injection, and transdermal delivery through topical cream application. The positive therapeutic effects of the LipoRu cream fabricated here in subcutaneous tumor‐bearing mice offer optimistic potential for the painless and non‐invasive treatment of both early‐stage and advanced skin cancers, as well as superficially located solid tumors.