Intranasal CRISPR lipid nanoparticles targeting MAPK9 attenuate neuroinflammation after traumatic brain injury

Microglial TLR7 contributes to traumatic brain injury-induced neuroinflammation in mice.

Targeted blood-brain barrier penetration for traumatic brain injury therapy via RXR/PPAR-driven microglial M2 polarization

As a leading global cause of death and disability, traumatic brain injury (TBI) triggers a complex secondary injury process leading to long-term neurological impairment. Current therapeutic efficacy is limited by the blood-brain barrier (BBB) and the absence of integrated approaches to address neuroinflammation and neuroregeneration. We designed a biomimetic nanomedicine (Ali-NPs@Mexo) by encapsulating alitretinoin(Ali)-loaded albumin nanospheres within mesenchymal stromal cell (MSC)-derived exosomal membranes. This platform exploits the natural BBB-crossing and inflammation-targeting capabilities of exosomes to enhance localized drug delivery. Mechanistic studies revealed that Ali-NPs@Mexo triggers RXR/PPAR signaling to promote M1-to-M2 microglial polarization, thereby mitigating acute inflammation. Moreover, it protects neurons by inhibiting reactive astrogliosis and supporting the growth of neural stem cells and oligodendrocytes. In vivo, Ali-NPs@Mexo significantly improved functional and cognitive outcomes in mice. This integrated strategy of targeted immune-modulation and neuro-regeneration provides a translatable framework for effective TBI intervention.

MSC-derived extracellular vesicle-associated miRNAs in CNS diseases: mechanisms of microglial polarization and therapeutic implications

Microglia-mediated neuroinflammation contributes to the pathogenesis of many central nervous system (CNS) diseases. After injury or infection, microglia can adopt pro-inflammatory programs that amplify neuronal damage. By contrast, reparative microglial states support inflammatory resolution, tissue repair and regeneration. Strategies that redirect harmful microglial activation toward reparative programs therefore have therapeutic relevance. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), particularly small EV-enriched preparations, are increasingly studied as low-immunogenicity carriers of regulatory cargo. EV-associated microRNAs (miRNAs) are among the major payloads implicated in immunomodulation. This review synthesizes how MSC-EV-associated miRNAs regulate microglial polarization and neuroinflammation through TLR/NF-κB, MAPK, JAK/STAT, PI3K/Akt and Wnt/β-catenin signaling. We discuss evidence from ischemic stroke, traumatic brain injury, spinal cord injury, Alzheimer’s disease and sepsis-associated encephalopathy, and highlight EV terminology, donor source, species context and translational comparability as key barriers for future development.

Targeting Microglial C5aR1 with PMX205 Attenuates Neuroinflammation and Improves Neurological Recovery After Intracerebral Hemorrhage

Non-viral targeted inducible nitric oxide synthase (iNOS) delivery to the brain for modulating sterile inflammation induced by ultrasound-mediated BBB opening

Focused ultrasound (FUS) combined with circulating microbubbles (MBs) enables noninvasive, spatially targeted opening of the blood–brain barrier (BBB) for drug and gene delivery. However, accumulating evidence indicates that even mild BBB opening parameters can induce sterile neuroinflammation, characterized by microglial activation and astrocytosis, which could pose a significant barrier to clinical translation. In this study, we explored whether localized NO production in the brain, derived by inducible nitric oxide synthase (iNOS) transfection, could modulate inflammatory responses associated with FUS-mediated BBB opening. iNOS plasmid DNA was delivered to the mouse hippocampus using cationic MBs and low-pressure FUS. BBB opening alone elicited a robust sterile inflammatory response without overt tissue damage. High-dose iNOS transfection further exacerbated inflammation and induced apoptosis, indicating dose-dependent neurotoxicity. In contrast, low-dose iNOS delivery resulted in minimal to no microglial accumulation, reduced astrocyte activation, and no detectable apoptosis or structural injury, despite successful opening of the BBB. These findings suggest that modest, localized NO production can suppress ultrasound-induced sterile inflammation in a dose-dependent manner. This work identifies a previously unrecognized anti-inflammatory role for low-level iNOS expression and suggests a straightforward strategy to improve the safety and therapeutic window of FUS-mediated BBB opening for neurotherapeutic applications.

Photobiomodulation of immune crosstalk rescues neuroinflammation in Alzheimer's disease models.

Peripheral immune cell infiltration and crosstalk with brain-resident cells critically drive Alzheimer's disease (AD)-associated neuroinflammation, highlighting its therapeutic potential. Here, we found that photobiomodulation (PBM) markedly reduced cerebral CD8+ T cells infiltration in the cortex of AD (APP/PS1 and 3×Tg) mice, thereby improving cognition, and alleviating AD-related pathology by mitigating neuronal damage and gliosis. Immunofluorescence and transcriptomic analyses revealed that PBM inhibited the release of chemokines and pro-inflammatory cytokines from microglia, reducing endothelial adhesion molecules-mediated T cell migration. Concurrently, reduced secretion of tumor necrosis factor-α, interleukin-1α, and complement component 1q by pro-inflammatory microglia further diminished neurotoxic A1 astrocyte induction. Genetic overexpression or pharmacological inhibition further validated that PBM disrupted microglia NOD-like receptor protein 3 inflammasomes activation, attenuating astrocyte reactivity and T cells recruitment. These findings collectively suggest that the PBM-induced modulation of crosstalk between microglia, astrocytes, and CD8+ T cells is closely related to cognitive improvement. Reprogramming central-peripheral immune crosstalk with PBM resolves neuroinflammation and restores cognition in AD models-a translatable strategy for combating neurodegeneration.