Nanomedicine for targeting crosstalk between nerves and cancer.

The emerging field of cancer neuroscience has revealed the nervous system as a dynamic regulator of tumors and the tumor microenvironment. Neural activity influences tumor progression through electrical signaling, neurotransmitter and neuropeptide release, and interactions with immune cells. The direction and magnitude of these effects vary according to neuronal subtype, receptor expression, target cell, and tumor context. Neural inputs may either promote or suppress tumor growth and anti-tumor immunity, although protumorigenic and immunosuppressive pathways remain the most extensively characterized. Conversely, tumors remodel neural circuits to accelerate their growth and trigger severe neurological complications, such as cancer pain. These bidirectional interactions make the nerve-cancer interface a compelling therapeutic target. Nanomedicine offers significant promise in this context, leveraging its adaptability in drug delivery. Specifically, surface functionalization allows targeted delivery of neuromodulators, precisely modulating the tumor-associated neural niche. Moreover, nanomedicine can be rationally designed to ensure biocompatibility, physiological stability, controlled release, and penetration across biological barriers. It can also co-deliver therapeutic and imaging agents for combined or theranostic applications. This review systematically summarizes the mechanisms underlying nerve-cancer interactions and evaluates their therapeutic potential through nanomedicine. We highlight emerging nanomedicine-based strategies for treating tumors and cancer pain, including single-modality neural modulation, multimodal combination therapies, and imaging-guided approaches. Finally, we address current challenges and future directions, aiming to inspire innovative approaches for comprehensive cancer therapy.