A stimuli-responsive mitochondria-targeted nanoplatform for glioblastoma therapy: modulating the blood-brain barrier and delivering precise chemotherapy

The blood brain barrier (BBB) is crucial for maintaining homeostasis within the central nervous system (CNS). Its impairment under pathological conditions significantly compromises the efficacy of chemotherapy for glioblastoma (GBM). Therefore, strategies to promote BBB functional recovery could provide a valuable adjunct to GBM chemotherapy. Mitochondria, the primary cellular "powerhouses", are key organelles regulating apoptosis. Mitochondrial dysfunction in either BBB or GBM cells is closely associated with barrier disruption and enhanced tumor cell apoptosis, respectively. This positions mitochondria as a promising dual target for modulating BBB integrity and enabling targeted chemotherapy. Celastrol (Cela), a natural pentacyclic triterpenoid isolated from the traditional Chinese medicine (TCM) Tripterygium wilfordii, has been shown to exhibit many pharmacological activities, including anti-tumor, anti-fibrosis, anti-inflammatory, immunomodulation, antioxidant, and neuroprotective effects. In addition, Cela has been widely used as a mitochondrial protector in CNS disorders, and it also safeguards endothelial cells from apoptosis, which helps maintain the structural and functional integrity of the BBB. However, the applications of Cels are still limited due to its poor water stability, non-specific distribution, low bioavailability, and high systemic toxicity. In this study, we developed a stimuli-responsive mitochondria-targeted nanoplatform encapsulating Cela, termed Cela@Lip-IRH, for the precise treatment of GBM. The incorporation of IR780 facilitated cellular uptake and promoted mitochondrial co-localization of Cela@Lip-IRH in both BBB and GBM cells in vitro. Furthermore, the nanoplatform exhibited enhanced BBB penetration and achieved specific accumulation in GBM tumors in vivo. We systematically investigated the anti-tumor efficacy and underlying mechanisms of Cela@Lip-IRH, focusing on mitochondrial function-dependent BBB restoration and the induction of tumor cell apoptosis. Collectively, this work provided novel therapeutic strategies and mechanistic insights for targeted GBM therapy, positioning Cela@Lip-IRH as a promising nanoplatform for modulating mitochondrial activity. Moreover, the combined strategy of BBB repair and chemotherapy may have broader implications for treating a range of neurological disorders.