Abstract
<title>Abstract</title> <p>Chronic stress is a known risk factor for glioma progression. However, the specific mechanisms involved remain unclear, posing a major obstacle to the development of targeted therapies. Our study reveals that chronic stress drives glioma progression by activating a self-reinforcing feedback loop between intratumoral neurons and astrocytes. Under stress, neuron-derived norepinephrine (NE) upregulates (brain-derived neurotrophic factor) BDNF expression in astrocytes. BDNF then promotes tumor growth and invasion, which further elevates microenvironmental NE levels, creating a vicious cycle. To disrupt this loop, we developed iRGD/A2-co-modified exosomes (iRA2-MBP) to co-deliver a BDNF antibody(aBDNF) and propranolol for enhanced brain tumor targeting. The BDNF antibody neutralizes target and reprograms macrophages, while propranolol induces immunogenic cell death and alleviates T cell exhaustion. In stress-bearing glioma mice, iRA2-MBP achieved a 27.85-fold higher intratumoral antibody accumulation than free antibody, reversed T cell exhaustion, and promoted immune activation, leading to 40% tumor regression, prolonged survival, and long-term immunological memory. In conclusion, this work identifies a stress-associated NE–BDNF signaling mechanism in glioma progression and presents an exosome-based immunomodulatory therapeutic strategy for stress-associated glioma.</p>