Pharmacological modulation of cGAS-STING-NLRP3 signaling by nano-immunomodulators in Alzheimer and Parkinson disease

Neuroinflammation is a central driver of neurodegeneration in Alzheimer's disease (AD) and Parkinson's disease (PD), driven by interconnected pathways involving microglial state dysregulation, inflammasome activation, cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling, impaired mitophagy, CD33-TREM2 imbalance, gut-brain axis disruption, and peripheral immune infiltration across a compromised blood-brain barrier (BBB). Conventional anti-inflammatory therapies remain limited by poor CNS delivery, inadequate cell specificity, and the inability to simultaneously modulate multiple inflammatory pathways. Nano-immunomodulators (NIMs) have emerged as a promising strategy to modulate CNS immunity in preclinical models. This review critically evaluates recent advances in NIM-based strategies for AD and PD, including intrinsically therapeutic nanomaterials, targeted delivery systems, and precision gene-regulatory platforms. Intrinsically therapeutic materials, such as polydopamine nanoparticles and biomimetic nanozymes, provide antioxidant and mitochondrial protective functions, whereas BBB-targeted systems, including nanobody-based platforms and engineered exosomes, enhance targeted CNS delivery. Nanotheranostics approaches integrate imaging capabilities with stimuli-responsive release, while precision interceptors aim to simultaneous regulate pathological processes such as amyloid-beta (Aβ)-associated inflammation and cGAS-STING activation. Emerging gene-delivery strategies, including TREM2 mRNA and CD33-targeting lipid nanoparticles, offer opportunities for microglial reprogramming but remain largely restricted to proof-of-concept and early preclinical stages. The review further discusses AI-driven nanomedicine optimization and advanced human-relevant models, including brain-on-a-chip systems and three-dimensional (3D) bioprinting, as tools to improve translational prediction. Currently, AI approaches primarily support candidate selection, formulation optimization, and mechanistic prediction rather than clinical validation. Major challenges for clinical advancement include achieving precise modulation of microglial states beyond the simplified M1/M2 framework, developing context-dependent regulation of NLRP3 and cGAS-STING pathways, establishing gut-CNS therapeutic strategies, improving pluripotent stem cell (iPSC)-based validation platforms, and defining long-term CNS safety frameworks. By integrating molecular mechanisms, AI-assisted nanomedicine, nanoparticle-enabled immune and gene modulation, and advanced preclinical models, this review provides a mechanistic and translational framework for advancing next-generation NIM strategies in AD and PD. This integrated perspective addresses the limitations of previous single-domain analyses focused either on neuroinflammation or nanotechnology and outlines key considerations for translating NIMs from experimental platforms toward clinical applications.