Abstract

The clinical utility of chemotherapy is often compromised by its limited efficacy and significant side effects. Addressing these concerns, we develop a self-assembled nanomicelle, namely SANTA FE OXA, which is composed of hyaluronic acid (HA) conjugated with ferrocene methanol (FC-OH), oxaliplatin prodrug (OXA({square})) and glycol-coupled linoleic acid (EG-LA). Targeted delivery is achieved as HA binds to the CD44 receptors that are overexpressed on tumor cells, facilitating drug uptake. Once internalized, hyaluronidase (HAase) catalyzes the digestions of the SANTA FE OXA, releasing FC and reducing OXA({square}) into an active form. Active OXA induces DNA damage, while simultaneously promoting intracellular hydrogen peroxide levels via cascade reactions. In parallel, FC disrupts the redox balance within tumor cells, inducing ferroptosis. The synergistic combination of cascade chemotherapy and self-sensitized ferroptosis therapy has demonstrated remarkable anti-cancer efficacy in both in vitro and in vivo models. Moreover, this SANTA FE OXA significantly mitigates the systemic toxicity commonly associated with platinum-based chemotherapeutics. Our findings suggest a compelling advancement in nanomedicine for enhanced cascade cancer therapy.