Synergistic Therapeutic Platform Combining Transcranial Low-Intensity Ultrasound Stimulation and Curcumin Load Liposome Ameliorates Cerebral Ischemia by Modulating Microglia Polarization-Mediated Neuroinflammatory Microenvironment

Successful restoration of blood supply still follows with serious secondary brain injury in cerebral ischemia reperfusion injury (CIRI). However, conventional management after CIRI exhibits numerous limitations.Transcranial low-intensity ultrasound stimulation (TLUS) has been extensively utilized in the field of neuromodulation owing to its characteristics of zero potential side effects, noninvasiveness, deep tissue penetration, and precise spatial targeting capability. Here, we develop a smart multifunctional ultrasound-responsive delivery system to regulate CIRI. Briefly, curcumin, a well-documented safe neuroprotective monomer derived from traditional Chinese medicine, is encapsulated into self-assembled liposomal nanocarriers (RRP@Lipo-Cur). These nanocarriers are modified with reactive oxygen species- and ultrasound-responsive functional elements, as well as neuron-targeting peptides, enabling targeted accumulation in ischemic penumbra and stimuli-responsive drug release. In the mouse model of middle cerebral artery occlusion/reperfusion (MCAO/r), the synergistic treatment of RRP@Lipo-Cur and TLUS significantly facilitated the polarization of microglia from the M1 to the M2 phenotype via the intracellular mitogen-activated protein kinase (MAPK) and nuclear factor κB signaling (NF-κB) pathways, which effectively promoted the establishment of an anti-inflammatory microenvironment in the ischemic penumbra, thereby providing neuroprotection for the damaged neurons. Furthermore, in comparison to single nanomaterial or TLUS interventions, synergistic treatment can optimally modulate neuroinflammation, safeguard injured neurons, and enhance the recovery of neurological function.