A Triple-Stage Precision Carbon Dot Nanogel With Cascade Activation for Spatiotemporally Controlled Chemo-Photodynamic Therapy.

Conventional chemotherapy is limited by poor cellular uptake and low tumor selectivity, often requiring high systemic doses that increase off‑target toxicity. Here we report a triple‑stage precision nanogel (CDX@nano) in which carbon dots (CDs) serve as organelle‑targeted delivery vehicles. The nanogel is surface-functionalized with indomethacin for tumor‑specific homing and encapsulates CDs conjugated with doxorubicin (DOX) via glutathione-cleavable disulfide linkages. Upon near-infrared irradiation, the CDs generate singlet oxygen, triggering nanogel disassembly, and rapid drug release. The liberated CDs accumulate in mitochondria, elevating reactive oxygen species and disrupting redox homeostasis, while DOX translocates to the nucleus to induce DNA damage. This cascade-activated, dual-compartment assault integrates photodynamic and chemotherapeutic modalities. In vitro, CDX@nano reduced tumor cell viability to 8.5% upon irradiation, showing approximately 4.5‑fold greater potency than non-targeted controls. In vivo, it achieved over 85% tumor growth inhibition with minimal systemic toxicity. This triple-stage platform offers a promising strategy to overcome key barriers in cancer therapy.