The revolutionary advent of genome editing has ushered in a new era for the treatment of genetic disorders, promising precise correction of mutations at the DNA level. However, despite its transformative potential, one of the most formidable challenges that has constrained its clinical translation is the difficulty of delivering these genome editors specifically to the affected tissues in living organisms. This limitation not only hampers the efficacy of genetic interventions but also raises critical safety concerns by posing risks of off-target effects in non-target tissues. Recent advancements in delivery mechanisms are beginning to overcome these barriers, heralding a future where genome editing therapies can be targeted with unprecedented precision, enhancing both their therapeutic impact and safety profiles.
Central to the success of genome editing in vivo is the necessity for targeted delivery systems that can shepherd the molecular machinery — including nucleases like CRISPR-Cas systems — precisely to diseased cells or tissues. Traditional approaches have relied on viral vectors such as adeno-associated viruses (AAVs), which offer efficient gene transfer capabilities but come with inherent limitations including immunogenicity, limited cargo capacity, and a lack of precise tissue tropism. These limitations constrain the range of diseases that can be tackled using viral vectors, especially for conditions that require delivery to less accessible or more sensitive organs.
In response, researchers have invested considerable effort into developing non-viral delivery platforms, such as lipid nanoparticles (LNPs), which have recently gained prominence due to their success in mRNA vaccines and their ability to encapsulate and protect genome editing components. The versatility of LNPs, including their capacity for surface modification with targeting ligands, makes them attractive candidates for achieving cell type-specific delivery. Nevertheless, achieving robust and efficient editing in the right tissue context in vivo remains a significant hurdle, necessitating further innovations in nanoparticle design and targeting strategies.
Beyond the carrier vehicles themselves, a deeper understanding of the biological barriers within the body — including the vascular endothelium, cellular membranes, and intracellular trafficking routes — is essential. Exploiting natural biological pathways for cellular uptake and trafficking holds promise for enhancing delivery fidelity and efficiency. For example, harnessing receptor-mediated endocytosis through conjugation of targeting moieties to the delivery vehicles allows for selective engagement with specific cell types, thereby minimizing off-target uptake and maximizing therapeutic index.
Concurrently, the emergence of engineered viral and non-viral delivery systems with enhanced selectivity and reduced immunogenicity has accelerated preclinical and clinical progress. Recent studies have demonstrated that engineered AAV capsids with altered tropism can improve delivery to particular tissues such as the central nervous system or muscle, expanding the repertoire of diseases amenable to gene editing therapies. Such refined vectors diminish the risk of immune responses while permitting lower dosing, which is critical for patient safety and the durability of therapeutic effects.
Another exciting frontier is the integration of genome editing with emerging bioengineering technologies, such as extracellular vesicles and cell-derived vehicles, which offer natural biocompatibility and the potential for intrinsic targeting capabilities. These biologically derived delivery systems can circumvent some of the immunological and biodistribution challenges confronting synthetic nanoparticles and viral vectors, representing a new paradigm for precision genome editing delivery.
The article under discussion synthesizes these preclinical breakthroughs and clinical advancements, highlighting how the interplay of molecular engineering, delivery vehicle optimization, and biological insight is converging to realize precision genome editing in vivo. Emphasizing a “magic bullet” approach, the review contemplates a future where genome editors are precisely deployed within the body to correct pathogenic mutations safely and effectively across diverse genetic diseases.
Critical to moving towards this goal is the development of modular and adaptable delivery platforms that can be tailored to individual diseases and patient-specific needs. Such platforms must be capable of delivering not only the nuclease enzymes but also guide RNAs and any necessary accessory proteins or cargos. The ability to co-deliver these components in defined stoichiometries and temporal patterns could significantly enhance editing outcomes and reduce unintended consequences.
Moreover, targeting genome editors with temporal control — enabling editors to be active only transiently and in the desired cell types — holds immense promise for improving safety by reducing exposure and off-target editing risks. Advances in inducible promoter systems and localized delivery technologies are contributing to this refined level of control and specificity.
The clinical translation of genome editing therapies also necessitates overcoming regulatory and manufacturing challenges linked to delivery technologies. Standardizing production methods for viral and non-viral vectors, ensuring batch-to-batch consistency, and demonstrating long-term safety are vital steps before widespread therapeutic use can be achieved. Encouragingly, growing clinical trial pipelines employing diverse delivery mechanisms underscore the field’s momentum and growing confidence in in vivo genome editing.
Safety considerations remain paramount, especially as genome editing moves beyond rare monogenic disorders to more prevalent or complex diseases. Tissue-specific delivery minimizes systemic exposure and reduces the risk of off-target mutagenesis, immune activation, and genotoxicity, which is crucial in maintaining the therapeutic window. Combining refined delivery with high-fidelity editing enzymes helps balance therapeutic efficacy with patient safety.
Looking forward, integration of artificial intelligence and high-throughput screening approaches to optimize delivery vehicles opens avenues to identify novel targeting ligands or nanoparticle formulations tailored for specific tissues or disease states. This data-driven approach accelerates discovery pipelines and fine-tunes delivery systems for maximal efficacy and safety.
The promise of targeted delivery also extends beyond therapeutic applications to fundamental biology and biotechnology. Precise in vivo genome editing opens possibilities for modeling disease states, developing gene-function studies, and creating better animal models that more accurately recapitulate human conditions. These advances underpin drug development and precision medicine endeavors.
In conclusion, the targeted delivery of genome editors in vivo represents a pivotal frontier that bridges the gap between molecular gene editing capabilities and real-world clinical implementation. As research converges on novel delivery mechanisms, refined biological targeting strategies, and enhanced control over editor activity, the vision of precise, safe, and effective genome editing therapies is rapidly becoming a tangible reality. This emerging paradigm promises to transform the therapeutic landscape of genetic diseases and unlock new horizons for medicine.
Subject of Research: Targeted delivery methods for genome editors to enhance precision and safety in in vivo applications.
Article Title: Targeted delivery of genome editors in vivo.
Article References:
Ngo, W., Wu, J.L.Y., Wasko, K.M. et al. Targeted delivery of genome editors in vivo. Nat Biotechnol (2026). https://doi.org/10.1038/s41587-025-02945-w
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41587-025-02945-w
Tags: adeno-associated viruses challengesadvancements in genetic interventionsCRISPR-Cas technologygenetic disorder treatmentnucleases delivery mechanismsoff-target effects in genome editingprecision genome editingprecision medicine and genome editingsafety profiles in gene therapytargeted in vivo delivery systemstherapeutic impact of genome editingviral vectors limitations
