This article systematically reviews recent advances in chemical delivery strategies—such as lipid nanoparticles, polymer-based carriers, and oligonucleotide conjugates—for genomic therapies targeting the brain. It emphasizes how structural design, high-throughput screening, and targeted modifications enhance blood-brain barrier (BBB) penetration and cell-specific delivery.
Literature Overview
The article, 'Chemical Strategies for Brain Delivery of Genomic Therapy,' published in Nature Reviews Chemistry, reviews and summarizes recent progress in chemical strategies for delivering genomic therapies to the central nervous system (CNS). The paper focuses on three major non-viral delivery platforms—lipid nanoparticles (LNPs), polymers, and oligonucleotide conjugates—and systematically discusses their chemical structures, functional group designs, targeting modifications, and therapeutic outcomes in animal models. The authors also highlight future directions for improving brain delivery efficiency through high-throughput screening, machine learning, and novel chemical modifications. The section is logically structured and ends with a full stop.Background Knowledge
Central nervous system (CNS) disorders such as Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), and Huntington’s disease are often caused by specific gene mutations or dysregulated gene expression, making them difficult to cure with conventional small-molecule drugs. Genomic therapies offer curative potential by modulating disease-causing genes at the DNA or RNA level through silencing, repair, or expression control. However, the blood-brain barrier (BBB) poses a major obstacle by highly restricting the entry of exogenous substances into brain tissue. Currently approved antisense oligonucleotide (ASO) drugs, such as nusinersen and tofersen, require invasive intrathecal injection, which results in uneven distribution. While viral vectors enable long-term gene expression, they face challenges including immunogenicity and limited re-administration. Therefore, developing safe, efficient, and re-dosable non-viral delivery systems has become a research priority. In recent years, lipid nanoparticles (LNPs) have gained significant attention due to their success in mRNA vaccines; polymer carriers can be chemically modified for targeted delivery; and oligonucleotide conjugates exploit ligand-receptor mechanisms to cross the BBB. These chemical strategies collectively form the core delivery technologies for next-generation brain-targeted gene therapies. Current challenges remain in improving brain enrichment after systemic administration, achieving cell-type specificity, minimizing off-target toxicity, and enabling scalable manufacturing. This review comprehensively outlines the chemical design principles and biological efficacy of these platforms, offering a complete chemical perspective and design blueprint for developing gene therapeutics capable of crossing the BBB.
Research Methods and Experiments
The authors conducted a systematic review of recent advances in chemical strategies across three major non-viral delivery platforms: lipid nanoparticles (LNPs), polymers, and oligonucleotide conjugates. For LNPs, the study summarizes the chemical design of the classic four-component structure (ionizable lipid, helper lipid, cholesterol, PEG-lipid) and highlights methods for rapidly evaluating LNP ability to cross the BBB using high-throughput screening techniques such as DNA barcoding, Transwell models, and organoid systems. The article also lists several BBB-penetrant small-molecule-derived lipids (e.g., tryptamine- or MK-0752-based BLNPs) and strategies to enhance targeting via antibody, peptide (e.g., RVG29), or surfactant surface modifications. Additionally, various administration routes—including intrathecal, intracerebral, intranasal, and focused ultrasound-assisted delivery—are systematically compared.Key Conclusions and Perspectives
Research Significance and Prospects
This review comprehensively summarizes current chemical design strategies for non-viral gene delivery systems in the treatment of brain disorders, emphasizing the structure–function relationships between chemical structures and biological outcomes. By systematically outlining recent advances in LNPs, polymers, and conjugates, it provides clear molecular design guidance for researchers.
Future research will increasingly rely on high-throughput screening and machine learning–assisted molecular design to accelerate the discovery of novel lipids and polymers. Achieving cell-type–specific delivery (e.g., neurons, astrocytes, microglia) will be key to improving therapeutic precision. Moreover, long-term safety, immunogenicity, and manufacturability of delivery systems require further evaluation. Coupled with emerging sequencing technologies and disease models, these chemical delivery platforms hold promise for advancing more gene therapies into clinical trials, potentially transforming the treatment landscape for neurodegenerative and psychiatric disorders.
Conclusion
This article systematically summarizes the pivotal role of chemical strategies in advancing brain delivery of genomic therapies. As three major non-viral platforms—lipid nanoparticles, polymers, and oligonucleotide conjugates—rational chemical design has significantly enhanced their ability to cross the blood-brain barrier. Notably, novel ionizable lipids, targeting ligand modifications, and bivalent structural designs have enabled efficient and durable gene regulation in animal models. These advances not only overcome limitations of traditional delivery methods but also open the door to systemic administration. In the future, integration of high-throughput screening and artificial intelligence will accelerate the discovery of optimal delivery systems. Furthermore, interdisciplinary collaboration will drive the translation of these chemical platforms from bench to bedside, offering curative solutions for intractable brain diseases such as Alzheimer’s disease and ALS. This review provides researchers in the gene therapy field with a comprehensive chemical perspective and design blueprint, marking the dawn of a new era in which brain-targeted gene therapies become increasingly precise and accessible.
