Complement at the Nano-Neuroimmune Interface: Implications for Opioid Use Disorder

The complement system is a central component of innate immunity with established roles in host defense and emerging functions in neurodevelopment, synaptic remodeling, and neuroimmune communication within the central nervous system (CNS). In parallel, advances in nanotechnology have enabled targeted strategies for CNS drug delivery but have also revealed that many nanomaterials interact with and activate complement, influencing biodistribution, safety, and inflammatory responses. Opioid use disorder (OUD) is increasingly recognized as a condition associated with chronic neuroimmune dysregulation involving glial activation, altered cytokine signaling, and blood-brain barrier (BBB) disruption. Although relatively few studies have directly measured complement activation in OUD, emerging transcriptomic, cellular, and inflammatory data suggest that complement pathways may intersect with opioid-induced neuroimmune signaling. This review synthesizes current knowledge at the intersection of complement biology, nanomedicine, and opioid-associated neuroimmune changes. It distinguishes well-established mechanisms of complement activation by nanomaterials from emerging evidence linking complement signaling to opioid exposure. It integrates complement pathways with opioid receptor and Toll-like receptor 4 (TLR4) signaling in glial cells and endothelial compartments, and discusses both beneficial and pathological roles of complement in the CNS. Finally, the therapeutic potential and limitations of complement-aware nanotechnology and complement modulation in CNS drug delivery and addiction neuroscience are outlined to guide translation of complement-targeted nanomedicines in addiction neuroscience.