Naphthalimide-based andrographolide nanoplatform suppresses ccRCC via targeting the HIF-2α/VEGF signaling axis

Constitutive activation of hypoxia-inducible factor-2α (HIF-2α) is a central oncogenic driver in clear cell renal cell carcinoma (ccRCC). In this work, a naphthalimide-based multifunctional nanoplatform was developed as a drug delivery system for andrographolide (AG) to improve its therapeutic specificity. The resulting system (NAI-1@AG) enabled intracellular delivery of AG and reduced ccRCC cell viability. Mechanistic studies showed that AG-loaded nanoparticles downregulated HIF-2α transcription, accompanied by decreased expression of its downstream target VEGF, as confirmed by qRT-PCR and ELISA analyses. Compared with free AG and non-targeted formulations, targeted AG-loaded nanoparticles showed improved anti-proliferative activity, suggesting enhanced pathway-specific inhibition. The nanoplatform also possesses ratiometric fluorescence sensing capability for tryptophan as an auxiliary function. Overall, this system provides a potential nanocarrier strategy for targeting the HIF-2α/VEGF signaling axis in ccRCC.