ROS-Autocatalytic Nanoplatform: Disrupting Astrocyte-Cancer Crosstalk to Improve Glioblastoma Therapy
Time：2026/9/11 16:59:29 Views：7
ROS-Autocatalytic Nanoplatform: Disrupting Astrocyte-Cancer Crosstalk to Improve Glioblastoma Therapy
Glioblastoma (GBM) is a highly malignant brain tumour with extremely poor prognosis. Abnormal intercellular crosstalk between astrocytes and tumour cells serves as a key microenvironmental basis that supports tumour metabolic reprogramming, fuels malignant progression and mediates therapeutic resistance. In this study, we report a ROS-responsive autocatalytic nanotherapeutic strategy that targets and blocks mitochondrial transfer from astrocytes to tumour cells, breaking the metabolic mutual?support loop essential for tumour survival. Given the hyper?metabolic features of GBM and the barriers imposed by the brain microenvironment, we constructed a blood?brain?barrier?penetrable ROS?responsive ferrocene?incorporated polymeric nanoplatform. It enables co?delivery of two bioactive agents and controlled drug release within the tumour microenvironment. On one hand, this nanosystem inhibits mitochondrial energy metabolism in tumour cells; on the other hand, it down?regulates TSP?1 signalling to disrupt the astrocyte?tumour communication network mediated by tumour microtubes and reprograms the immunosuppressive tumour microenvironment. This work provides a translatable nanotherapeutic strategy to overcome therapeutic resistance in glioblastoma. The related findings, entitled ROS?Autocatalytic Nanoplatform Interfering Astrocyte?Cancer Crosstalk and Enhancing Glioblastoma Therapy, have been published in the international academic journal Nature Communications.
Glioblastoma exhibits profound metabolic plasticity and tends to relapse even after surgical resection, radiotherapy and chemotherapy. As critical stromal cells in the brain, astrocytes can transfer mitochondria to GBM tumour cells via tumour microtubes, supplying energy substrates, remodelling the metabolic phenotype of tumour cells and promoting tumour?initiating capacity as well as therapeutic resistance. Mitochondrial?transfer?driven intercellular crosstalk is a major contributor to the intractability of glioblastoma. Conventional therapeutic approaches mainly target tumour cells themselves and rarely interfere with the metabolic mutual?support loop between astrocytes and tumour cells. Simultaneously perturbing tumour mitochondrial function and disrupting abnormal stroma?tumour communication represents an urgent unmet challenge for glioblastoma treatment.
Targeting mitochondrial transfer between astrocytes and GBM cells, we developed a ROS?autocatalytic nanoplatform (GS@DFP) capable of crossing the blood?brain barrier. Modified with DHA, the nanoplatform hijacks GLUT1 transporters to achieve enrichment across the blood?brain barrier. Upon arrival at tumour sites, it responds to elevated intracellular ROS levels to trigger drug release and initiate the Fenton reaction. The co?loaded S?Gboxin inhibits mitochondrial complex V and depletes cellular ATP in tumour cells. Galunisertib suppresses the TGF?β/SMAD signalling axis, down?regulates TSP?1 expression, impairs tumour microtube formation and blocks mitochondrial transfer from astrocytes to glioblastoma cells. This nanosystem concurrently targets tumour mitochondrial vulnerabilities and pathological intercellular communication, remodels the immunosuppressive tumour microenvironment and markedly improves therapeutic outcomes against glioblastoma.
Yun Chen, a PhD candidate of the class of 2026 in our group, is the first author of this manuscript. Professor Tao Sun serves as the corresponding author, and Professor Chen Jiang is the co?corresponding author. This research was supported by the National Natural Science Foundation of China and several research programmes of Shanghai Municipality.
Link: https://www.nature.com/articles/s41467-026-77395-2
