Near-infrared light-triggered, self-amplifying targeted drug-delivery platform achieves precision treatment of retinoblastoma.
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The management of advanced retinoblastoma (RB), the most common pediatric intraocular cancer, is severely limited by the toxic side effects of conventional chemotherapy and the surgical radicality of enucleation. To address this, we engineered a tumor-specific, Reactive Oxygen Species (ROS)-responsive nano-co-delivery system that synergizes chemotherapy and Photodynamic Therapy (PDT) for precise and potent RB treatment. We designed a dimeric cabazitaxel (CTX) prodrug linked via a thioketal (TK) bridge, which is co-assembled with the photosensitizer chlorin e6 (Ce6) into stable nanoparticles. These nanoparticles are further functionalized with a cRGD peptide on their surface for active targeting of integrin αvβ3, which is overexpressed in RB. Upon accumulation at the tumor site and exposure to near-infrared (NIR) light, Ce6 generates a burst of cytotoxic ROS, initiating PDT-mediated cell death. Crucially, this exogenous ROS surge acts as a molecular trigger to cleave the TK linkers, on-demand releasing active CTX monomers directly within the tumor microenvironment. This ROS-triggered drug release creates a powerful positive feedback loop, amplifying the therapeutic effect. In vitro, the cRGD-decorated nanoparticles demonstrated superior cellular uptake and potent cytotoxicity against Y79 RB cells upon irradiation. In an orthotopic xenograft RB mouse model, the targeted nano-platform showed enhanced tumor accumulation, deep tissue penetration, and complete tumor ablation after NIR irradiation, with no observable systemic toxicity. This self-amplifying strategy represents a paradigm shift in targeted RB therapy, offering a highly precise and effective alternative to current standard-of-care treatments.