Molecular velcro for precision genome repair

Nature Communications volume 17 , Article number: 7560 ( 2026 ) Cite this article

Base editing promises transformative therapies for genetic disease, but delivery constraints have limited clinical translation. Mu and colleagues show that programmable coiled-coil assembly can create highly efficient split base editors and demonstrate its in vivo functionality.

Precise genome editing has long represented one of the central ambitions of molecular medicine. The development of CRISPR/Cas systems transformed that vision into a realistic therapeutic strategy by enabling programmable targeting of virtually any genomic sequence 1 . The first generation of CRISPR nucleases depended on the formation of double-strand DNA breaks, introducing risks associated with unpredictable repair outcomes, chromosomal rearrangements and genotoxicity. For many biomedical applications, particularly therapeutic correction of pathogenic point mutations, a more precise approach was needed.

Base editing fundamentally changed the landscape of genome engineering by enabling direct chemical conversion of selected DNA bases into another without generating double-strand breaks 2 , 3 , 4 . Cytosine and adenine base editors can collectively address a large fraction of known pathogenic mutations, creating extraordinary opportunities for the treatment of inherited disorders, cancer, cardiovascular and infectious diseases 3 . Early therapeutic studies have already demonstrated durable editing in vivo, including clinically relevant targeting of PCSK9 to lower cholesterol levels 5 . However, despite remarkable progress in efficiency and specificity, the field has encountered a persistent bottleneck in the delivery of relatively large base editors.

In Nature Communications, Mu and colleagues report an elegant solution to this problem by engineering coiled-coil-mediated split base editors (CC-BEs) that self-assemble inside cells through programmable pairwise coiled-coil peptide interactions 6 . Their study introduces a modular architecture for genome editing that not only overcomes viral packaging constraints but also unexpectedly improves editing performance in several configurations. The work represents an important conceptual advance at the intersection of synthetic biology and therapeutic genome engineering.

The challenge addressed by Mu et al. is substantial. Widely used Streptococcus pyogenes Cas9 (SpCas9)-derived base editors are too large to fit within the approximately 4.7-kb packaging limit of adeno-associated viral (AAV) vectors, which remain among the most clinically relevant platforms for in vivo gene delivery.

Several approaches have attempted to solve this limitation. One strategy employs split inteins that covalently splice editor fragments after delivery or using a chemically induced dimerization (CID) to control the activity of the deaminase TadA-8e 7 , 8 . Another seeks to develop increasingly compact CRISPR nucleases. Although both directions produced important advances, they also introduced tradeoffs involving efficiency, flexibility, targeting range or engineering complexity.

Mu and colleagues instead exploit a principle of programmable molecular self-assembly that has become increasingly influential in synthetic biology. Their system separates the catalytic and targeting components of base editors into independently deliverable modules linked through engineered coiled-coil peptide heterodimers 9 . Once inside the cell, the complementary coiled-coil peptides associate with high specificity, effectively reconstructing a functional editing complex. This approach replaces irreversible covalent reconstitution with dynamic molecular assembly. In addition to facilitating protein domain folding, the approach also enables the exchange of DNA processing domains at the DNA targeting site.

Coiled-coil interactions have emerged as highly versatile building blocks for protein engineering because they provide programmable and orthogonal interaction interfaces 9 . Over the past decade, engineered coiled-coil systems have enabled the design of protein origami architectures, intracellular scaffolds, synthetic condensates, and programmable signaling assemblies 10 , 11 , 12 , 13 , 14 .

Recent studies, including the CCExo system developed by Lainšček and colleagues, demonstrated that coiled-coil-mediated higher-order assemblies can support programmable intracellular organization and functional reconstitution of a CRISPR system with exonucleases, which performed better than direct protein fusion 15 . The work by Mu et al. now extends this design philosophy directly into genome engineering.

Importantly, the strategy proved to be highly generalizable. The authors successfully constructed coiled-coil versions of cytosine base editors (CC-CBEs), adenine base editors (CC-ABEs), TadCBEs, ABE9 systems, AYBE transversion editors and NG-PAM-compatible variants. Such breadth is notable because many genome-engineering innovations function only within narrow architectural constraints.

Even more striking was the observation that several coiled-coil systems outperformed their full-length counterparts. Some CC-CBEs achieved editing efficiencies up to 9.6-fold higher in HEK293T cells and 12.4-fold higher in porcine fibroblasts.

This finding suggests that modular assembly may provide benefits extending beyond delivery alone. Structural modelling using AlphaFold3 indicated that coiled-coil-mediated organization could generate more favorable spatial positioning of catalytic domains such as APOBEC3 and UGI. In other words, fragmentation and reassembly may sometimes improve enzyme architecture rather than merely preserving it.

The implication is profound as future editor design may increasingly rely on programmable supramolecular organization instead of continuous polypeptide optimization alone. The availability of multiple orthogonal coiled-coil modules also enables recruitment of multiple diverse protein domains at selected stoichiometries.

The therapeutic demonstrations in the study underscore the clinical significance of the approach. Using dual-AAV delivery, the authors achieved efficient editing of the Pcsk9 locus in mouse liver, reaching editing frequencies approaching 79%. Such efficiencies compare favorably with existing in vivo editing systems and reinforce the attractiveness of base editing for therapies from inherited genetic disorders to cardiovascular diseases, highlighting its considerable potential for future clinical translation.

The application to Duchenne muscular dystrophy (DMD) is particularly compelling. By delivering an NG-compatible CC-ABE system using dual AAV9 vectors, the authors restored dystrophin expression in ΔEx51 mice through exon-skipping-mediated reframing of the Dmd transcript (Fig. 1 ).

The base editor is functionally separated into two components and each fused to complementary coiled-coil heterodimers and packaged into separate AAV vectors. Upon co-delivery, coiled-coil interactions mediate intracellular reconstitution of the active editor, enabling targeted nucleotide conversion. The platform demonstrates broad compatibility across multiple base editor chemistries. CC-mediated split editors achieved robust editing efficiencies in vitro, in some cases outperforming intact editors, particularly for cytidine base editing. In vivo proof-of-concept studies using dual-AAV delivery demonstrated efficient editing in mouse models, editing at the Pcsk9 locus in liver and correction of Dmd in a Duchenne muscular dystrophy model. Created in BioRender. Lainscek, D. (2026) https://BioRender.com/zuhb98q “.

Muscle tissue remains among the most difficult therapeutic targets for genome engineering because efficient systemic delivery to skeletal and cardiac muscle is challenging. While lipid nanoparticles have transformed liver-directed editing, their utility in muscle and heart remains limited. The ability to preserve high-efficiency editors within AAV-compatible architectures therefore remains clinically important despite growing interest in nonviral delivery technologies.

The broader importance of this work may lie in the emerging concept of modular genome engineering. Historically, genome editors have largely been designed as monolithic proteins. Progress was driven by improved nucleases, optimized deaminases and enhanced specificity variants. Mu and colleagues instead demonstrate the power of distributing editing functions across independently engineered modules connected through programmable molecular interactions.

This architecture opens several exciting future directions. First, modular editors may enable conditional or context-dependent assembly. Different components could potentially be expressed under cell-state-specific promoters, activated by disease-associated signals or localized selectively to defined intracellular compartments before assembly. Second, modular assembly may improve safety. This study already suggests that distinct coiled-coil configurations influence editing specificity and off-target behavior. Dynamic or inducible assembly could therefore become a route toward temporally controlled editing activity. Third, the strategy appears extensible to other editing modalities. Indeed, coiled-coil-mediated architectures have already begun to expand toward prime editing systems, suggesting the emergence of a broader family of programmable modular editors.

More generally, this work exemplifies the convergence of modular protein design and genome engineering. The future of therapeutic editing may depend not only on catalytic precision but also on the ability to dynamically organize molecular components within living cells.

Despite its promise, important challenges remain. Dual-AAV systems still require efficient co-transduction of two vectors, complicating manufacturing and dosing strategies. In addition, although whole-genome sequencing suggested broadly comparable off-target profiles between CC-BEs and conventional editors, some configurations exhibited elevated guide-independent editing activity. Continued optimization will therefore be essential before therapeutic translation.

The field is also rapidly advancing toward compact single-vector systems based on hypercompact nucleases and alternative delivery technologies. Future therapeutic platforms will likely involve complementary strategies tailored to different tissues and disease contexts rather than a single universal solution. Nevertheless, the work of Mu and colleagues demonstrates that programmable molecular assembly can solve problems in genome engineering while simultaneously creating opportunities for new editor architectures.

In that sense, coiled-coil-mediated base editing represents more than a delivery innovation. It signals a transition from static engineered enzymes toward dynamic, modular molecular systems assembled directly inside living cells. That transition may play an important role in the next era of genome engineering.

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