Bridging immune-neurovascular crosstalk via the immunomodulatory microspheres for promoting neural repair

The crosstalk between immune cells and the neurovascular unit plays a pivotal role in neural regeneration following central nervous system (CNS) injury. Maintaining brain immune homeostasis is crucial for restoring neurovascular function. In this study, an interactive bridge was developed via an immunomodulatory hydrogel microsphere to link the interaction network between microglia and the neurovascular unit, thereby precisely regulating immune-neurovascular crosstalk and achieving neural function recovery. This immunomodulatory crosstalk microsphere (MP/RIL4) was composed of microglia-targeted RAP12 peptide-modified interleukin-4 (IL-4) nanoparticles and boronic ester-functionalized hydrogel using biotin-avidin reaction and air-microfluidic techniques. We confirmed that the immunomodulatory microspheres reduced the expression of pro-inflammatory factors including IL-1β, iNOS, and CD86, while upregulating levels of anti-inflammatory factors such as IL-10, Arg-1, and CD206 in microglia. In addition, injection of the MP/RIL4 significantly mitigated brain atrophy volume in a mouse model of ischemic stroke, promoted neurobehavioral recovery, and enhanced the crosstalk between immune cells and the neurovascular unit, thus increasing angiogenesis and neurogenesis of stroke mice. In summary, the immunomodulatory microspheres, capable of orchestrating the interaction between immune cells and neurovascular unit, hold considerable therapeutic potential for ischemic stroke and other CNS diseases. The immune-neurovascular crosstalk bridge via the immunomodulatory microsphere (MP/RIL4) was constructed, which could induce the transformation of microglia into an anti-inflammatory phenotype, and link their interaction with neurovascular unit, ultimately succeeding to promote angiogenesis and neurogenesis in ischemic stroke model mice. [Display omitted] •Immunomodulatory microspheres (MP/RIL4) held great anti-inflammatory effects in vitro and in vivo.•MP/RIL4 mitigated brain atrophy volume and promoted neurobehavioral recovery for a long-time of ischemic stroke mice.•MP/RIL4 increased angiogenesis and neurogenesis via enhancing immune-neurovascular crosstalk of ischemic stroke mice.