Abstract
Background: Bone marrow serves as a source and reservoir of immune cells and plays a critical role in central nervous system diseases. Nociceptive neurons are widely distributed in the bone marrow, but their post-infarction changes and immunological functions remain largely unexplored. Methods: A mouse model of middle cerebral artery occlusion (MCAO) and human skull bone marrow samples from stroke patients were analyzed. Calcitonin gene-related peptide (CGRP) signaling was manipulated via receptor knockout and targeted nanoparticle delivery. Immune responses were evaluated primarily through flow cytometry, immunofluorescence, and single-cell RNA sequencing. Results: Activation of nociceptive neurons after cerebral infarction promoted myeloid-biased hematopoiesis in the bone marrow and increased infiltration of myeloid cells into brain tissue, resulting in anti-inflammatory and neuroprotective effects. This regulatory mechanism was mediated by CGRP, which enhanced the proliferation and mobilization of downstream myeloid-derived suppressor cells (MDSC), ultimately improving stroke outcomes. To overcome the hypotensive side effects of CGRP, we employed aged neutrophil membrane-coated nanoparticles for its targeted delivery to bone marrow, achieving sustained release and enhanced efficacy. Conclusion: Nociceptive neurons critically modulate post-stroke bone marrow immune responses by releasing CGRP and activating MDSC. Targeted CGRP delivery to bone marrow represents a promising strategy to suppress neuroinflammation and improve neurological recovery after cerebral infarction.