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Life sciences · Journal article
Advanced Functional Materials · October 15, 2026
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ABSTRACT Tumor heterogeneity remains a major translational challenge for targeted therapies, particularly those employing multi‐targeted precision strategies. To overcome this barrier and ensure both high tumor‐specificity and robust clinical efficacy, we designed CBT‐NM‐PPa‐cRGD, a photodynamic therapy (PDT)‐initiated, self‐amplifying prodrug engineered for potent, multi‐cascade tumor therapy. This prodrug incorporates a cRGD ligand to actively target α v β 3 integrin‐overexpressing cancer cells. Upon cellular internalization and laser irradiation, the elicited PDT effect activates caspase‐3 (Casp3). Casp3‐mediated cleavage combined with glutathione (GSH) reduction initiates a biocompatible click condensation to drive the intracellular self‐assembly of nitrogen mustard (NM)‐loaded nanoparticles, leading to a substantial enhancement in drug retention and local concentration. Subsequently, the azoreductase‐triggered release of NM induces tumor inhibition while further elevating Casp3 levels, thereby establishing a self‐perpetuating cascade that sustains the self‐assembly process. Moreover, PDT‐exacerbated tumor hypoxia accelerates azoreductase‐mediated NM release, fueling this positive feedback loop. The systematic in vitro and in vivo evaluations demonstrate that this PDT‐primed, enzyme‐controlled self‐amplifying strategy provides superior tumor suppression, exceptional targeting specificity, and minimal systemic toxicity, offering a transformative paradigm for precision cancer therapy.