OBJECTIVE: The exacerbation of extreme high-temperature events due to global climate change poses a significant challenge to public health, particularly impacting the central nervous system through heat stroke. This study aims to develop Poly(amidoamine) (PAMAM) nanoparticles loaded with curcumin (PAMAM@Cur) to enhance its therapeutic efficacy in hypothalamic neural damage in a heat stroke model and explore its potential mechanisms. METHODS: Curcumin (Cur) was encapsulated into PAMAM nanoparticles through a hydrophobic interaction method, and various techniques were employed to characterize their physicochemical properties. A heat stroke mouse model was established to monitor body temperature and serum biochemical parameters, conduct behavioral assessments, histological examinations, and biochemical analyses. Transcriptomic and proteomic analyses were performed to investigate the therapeutic mechanisms of PAMAM@Cur, validated in an N2a cell model. RESULTS: PAMAM@Cur demonstrated good stability, photostability, cell compatibility, significant blood-brain barrier (BBB) penetration capability, and effective accumulation in the brain. PAMAM@Cur markedly improved behavioral performance and neural cell structural integrity in heat stroke mice, alleviated inflammatory responses, with superior therapeutic effects compared to Cur or PAMAM alone. Multi-omics analysis revealed that PAMAM@Cur regulated antioxidant defense genes and iron death-related genes, particularly upregulating the PCBP2 protein, stabilizing SLC7A11 and GPX4 mRNA, and reducing iron-dependent cell death. CONCLUSION: By enhancing the drug delivery properties of Cur and modulating molecular pathways relevant to disease treatment, PAMAM@Cur significantly enhances the therapeutic effects against hypothalamic neural damage induced by heat stroke, showcasing the potential of nanotechnology in improving traditional drug efficacy and providing new strategies for future clinical applications. SIGNIFICANCE: This study highlights the outlook of nanotechnology in treating neurological disorders caused by heat stroke, offering a novel therapeutic approach with potential clinical applications.