Neuron-targeting piezoelectric microneedles disrupt pro-tumorigenic neuron-immune crosstalk and restore anti-tumor immunity in melanoma

Neuroimmunology has garnered significant attention due to its role in immune regulation, particularly in cancer, where infiltrating neurons can influence antigen presentation, T-cell activation, and cancer metastasis, ultimately leading to an inadequate immune response. Here, we integrate manganese-doped titanium-based metal-organic framework (MOF) piezoelectric materials (MT), coated with neuron-derived membranes from dorsal root ganglia, into microneedles (MN) to create a piezoelectric microneedle (MT MN) patch designed to disrupt neuron-immune crosstalk in melanoma. A single administration of MT via microneedle patch stably deposits the MT at the melanoma site in female mice to accelerate the nociceptor neurons targeting. Upon moderate ultrasound stimulation, the MT facilitates the internalization of TRPV1 and activates the cGAS-STING pathway, resulting in the reduction of Ca2+ influx in nociceptor neurons. This ultimately limits the production of calcitonin gene-related peptide (CGRP) and substance P (SP). Consequently, to rescue the tumor immune microenvironment damaged by infiltrated neurons, MT MN is utilized to inhibit the growth and infiltration of nociceptor neurons, highlighting a promising manner for interfering neuron-immune crosstalk in melanoma to enhance cancer immunotherapy. Activation of nocireceptors can contribute to immunosuppression in cancer. Here the authors report the design and characterization of nociceptor neuron-targeting piezoelectric microneedles, showing disruption of pro-tumorigenic neuron-immune crosstalk and reinvigoration of anti-tumor immunity in melanoma.