Cathepsin B-Activated Prodrug for Precision Tumor Theranostics.

In response to the systemic toxicity associated with chemotherapeutic agents and the diverse characteristics of the tumor microenvironment, we present an innovative theranostic prodrug system, designated NM-001. NM-001 specifically targets the overexpressed integrin ανβ3 on tumor cells via the cRGD peptide, facilitating internalization into lysosomes. Subsequently, cathepsin B selectively cleaves the GFLG peptide, triggering an intramolecular self-elimination reaction that generates NM-002 with near-infrared (NIR) emission and releases chlorambucil (CLB). Concurrently, the fluorescence property undergoes a transition from green to NIR emission, enabling precise monitoring of the drug delivery and release process, thereby establishing a dual-channel optical feedback mechanism. This mechanism allows for real-time, in situ differentiation of drug delivery and release dynamics at the cellular level. Both in vitro and in vivo studies have demonstrated that NM-001 exhibits high selectivity and substantial antitumor efficacy against tumor cells, presenting a promising novel approach for personalized diagnosis and therapy.