Peptide-Nanoparticle Platforms for Antisense Therapeutics: A Coarse-Grained Modeling Approach to Brain Delivery

Abstract

Traumatic brain injury (TBI) is a leading cause of long-term neurological deficits, often resulting in complex, unresolved molecular and cellular dysfunctions. Among these, gene–circuit disruptions—particularly those affecting neuroinflammation, oxidative stress, and mitochondrial dynamics—have emerged as critical mediators of post-traumatic neuropathology. In this study, we utilized artificial intelligence (AI)-driven proteomics and RNA sequence integration to map altered signaling pathways following TBI. Computational predictions identified specific gene–circuit nodes susceptible to therapeutic intervention, including redox-sensitive mitochondrial regulators and genes involved in the neuroimmune interface. Importantly, although our analyses are derived from rodent models, the conserved signaling pathways and regulatory circuits identified here provide a translational window with strong relevance to human TBI pathophysiology, thereby bridging preclinical findings with potential therapeutic application. Based on these insights, we designed a suite of responsive nanoparticle formulations optimized in silico for targeted delivery to dysregulated brain regions. These carriers incorporated ligands targeting disrupted circuits and incorporated redox-sensitive release mechanisms. Our platform demonstrates the feasibility of a closed-loop, data-guided strategy that integrates AI-based gene network profiling with rational nanocarrier design. This approach provides a scalable framework for precision neurotherapeutics, particularly for complex disorders such as TBI where conventional monotherapies have proven inadequate. © 2026 Elsevier Ltd.