Introduction: Why delivery platforms matter in CRISPR medicine
CRISPR-based therapies hold immense promise for treating a wide range of diseases, but their success hinges not only on the gene-editing tool itself but also on how the therapeutic payload reaches target cells. With nucleic acid–based CRISPR medicines, delivery is as crucial as the editing technology. While viral vectors such as adeno-associated viruses (AAVs) have played a foundational role, their limitations—payload capacity, pre-existing immunity, and potential safety concerns—have spurred the search for alternative delivery strategies. Lipid nanoparticles (LNPs) have emerged as a leading non-viral platform for in vivo CRISPR delivery, bringing advantages in manufacturability, safety, and dosing flexibility.
Lipid nanoparticles: composition and mechanism for CRISPR delivery
LNPs are small, uniform particles (roughly 50–120 nm) engineered to encapsulate nucleic acids and ferry them into cells. A typical LNP comprises three key components: ionisable lipids, structural lipids (phospholipids and cholesterol), and steric stabilizers such as PEG-lipids. The ionisable lipid plays a central role in RNA delivery: it is positively charged during formulation to enable efficient encapsulation, then neutral in physiological conditions to reduce toxicity. Once the particle is endocytosed by a cell, the acidic endosomal environment protonates the ionisable lipid, promoting endosomal disruption and release of RNA into the cytoplasm where the CRISPR machinery can act.
PEG lipids stabilize the particle during manufacturing and storage and gradually shed after administration, aiding cellular uptake and cargo release. The careful balance of these components is essential to maximize delivery efficiency while minimizing adverse effects.
From siRNA to CRISPR: evolving LNP payloads
The journey began with siRNA therapies, such as Onpattro®, which was approved in 2018 to treat hereditary transthyretin amyloidosis. This milestone demonstrated that LNPs can safely deliver nucleic acids in humans and sparked broader exploration of LNPs for diverse payloads, including mRNA vaccines and CRISPR components. Today, LNP platforms support siRNA, mRNA, and even co-delivery of mRNA with guide RNA for CRISPR-Cas9 editing, underscoring their versatility for gene-editing medicines.
Why LNPs can surpass viral vectors for CRISPR delivery
LNPs offer several advantages over viral systems. Pre-existing immunity to AAV capsids can limit repeat dosing and reduce effectiveness, whereas LNPs generally exhibit lower immunogenicity, enabling multiple administrations—an important feature for achieving therapeutic dosing through “dosing to effect.” In contrast to viral vectors that can drive long-term or permanent expression, LNP-based CRISPR delivery yields transient expression of the editing machinery, reducing off-target risks. Manufacturing viral vectors is often lengthy and complex, while LNP production can be rapid and scalable, with potential to shorten timelines from weeks to days or hours for personalized therapies.
Clinical milestones and real-world impact
One landmark moment came in 2025 when a single-patient trial at the Children’s Hospital of Philadelphia and the University of Pennsylvania used an LNP-based, personalised CRISPR approach to treat severe carbamoyl-phosphate synthetase 1 deficiency in an infant. Delivered using an Acuitas formulation with ionisable lipid ALC-0307 and PEG-lipid ALC-0159, the therapy involved escalating doses with no serious adverse events and a six-month development window. This trial illustrates how an approved delivery platform can accelerate personalized, rapid-response gene-editing therapies and demonstrates the value of cross-functional partnerships between delivery developers and payload manufacturers to compress development timelines.
Looking ahead, DARPin-conjugated LNPs and other targeting strategies show promise for expanding delivery beyond the liver, enabling edits in diverse cell types such as certain immune cells. Repeated dosing safety studies in non-human primates support the feasibility of adjusting treatment plans to achieve optimal outcomes while maintaining patient safety.
Future directions and broader accessibility
Researchers are pursuing several exciting avenues to broaden the reach of LNP-CRISPR therapies. Expanding tissue targeting beyond the liver, improving safety profiles for repeated dosing, and applying LNP-CRISPR in oncology and cardiovascular diseases are active areas of investigation. A critical objective is to make gene-editing medicines more accessible, reducing costs and simplifying manufacturing to ensure that life-changing therapies reach patients across diverse socioeconomic backgrounds. Establishing a robust, clinically approved LNP delivery platform will help drive faster development, scalable production, and lower barriers to patient access while maintaining rigorous safety standards.
Conclusion: LNPs as a linchpin for the future of CRISPR medicines
Lipid nanoparticles stand at the forefront of non-viral CRISPR delivery, offering a practical, scalable, and safer pathway to in vivo gene editing. By enabling transient expression, reducing immunogenicity, and accelerating manufacturing, LNPs help unlock the full potential of CRISPR therapies. As research advances and collaborations deepen, LNP-based CRISPR delivery is poised to expand the range of treatable diseases and bring personalized, precise genetic medicines to more patients worldwide.