Mitigating Cancer Therapy-Related Cognitive Impairment by Targeted Activation of Undruggable Phosphatase.

Cancer therapy-related cognitive impairment (CTRCI) is a debilitating neurotoxic condition adversely impacting cancer patients during and post-cancer treatments. The cancer treatments linked to CTRCI include chemotherapy, hormone therapy, targeted therapy, and immunotherapy. Despite CTRCI severely affecting the psychological and social, cognitive functions, and the overall quality of life of cancer survivors, no effective medications are available currently. Our prior studies have indicated hippocampal tyrosine phosphatase protein tyrosine phosphatase receptor type O (PTPRO) as a putative target for CTRCI. However, phosphatase is historically considered undruggable, and delivering drugs across the blood-brain barrier (BBB) is challenging. Here, we developed a novel delivery system using neuron-targeted extracellular vesicles (EVs) engineered with a neuron-specific peptide rabies virus glycoprotein (RVG) to transport a small activating RNA (saRNA) targeting Ptpro (RVG-EVs-saPtpro). We evaluated the stability, dynamic distribution, cytotoxicity, and brain specificity of RVG-EVs-saPtpro in cellular and animal models. A single intravenous injection of RVG-EVs-saPtpro resulted in sustained elevation of PTPRO in the brain for at least 28 days in CTRCI mice. More importantly, RVG-EVs-saPtpro significantly alleviated CTRCI symptoms by enhancing neuronal survival, neurogenesis, and synaptic plasticity. These findings highlight the potential of RVG-EVs-saPtpro system for targeted treatment of CTRCI.