Self-assembled nanocomplexes of polyphenol-modified prodrugs and transferrin enable cascade-targeted and redox-activated chemotherapy.

The development of simple, efficient, and actively targeted drug delivery systems remains a significant challenge for clinical translation. Here, we propose a carrier-free nanodrug platform based on polyphenol-modified prodrugs with self-assembly and ligand-adsorption capabilities. Specifically, two gallic acid-modified Cabazitaxel (CTX) prodrugs were synthesized: a reduction-responsive prodrug (CSG) and a non-responsive control (CCG). These prodrugs spontaneously assembled into nanocomplexes, and transferrin (Tf) was non-covalently adsorbed onto their surfaces via polyphenol-protein interactions, forming Tf-functionalized nanocomplexes (Tf NCs). This ligand-anchoring strategy endowed the system with Tf receptor (TfR)-mediated active targeting and enhanced colloidal stability. Notably, the CSG@Tf NCs exhibited a cascade targeting effect: prolonged circulation, tumor-specific accumulation via TfR recognition, and glutathione (GSH)-triggered CTX release in the tumor microenvironment. In vitro and in vivo studies confirmed that CSG@Tf NCs significantly improved antitumor efficacy while reducing systemic toxicity. This work presents a novel, carrier-free, and dual-functional strategy for constructing targeted prodrug nanomedicines with strong translational potential.