Delivering on the Promise of CRISPR

June 3, 2026 by Maarten Walmagh

Focus on Delivery Strategies in Cell & Gene Therapy Applications

Targeted delivery of CRISPR-based therapies or therapeutics to the right tissue or cell type in the human body is a huge challenge. Specifically, for in vivo based gene editing therapies, which seems to be the future of cell & gene therapies, the delivery method is even more crucial than for ex vivo applications.

It seemed to be a recurrent topic when discussed recently at the CRISPRMed26 conference. The science and developments around the payloads portion has evolved to a high level, but delivery is not really following and could definitely need a boost to keep up. The important aspects of an ideal delivery method are:

• Efficiency
• Specificity
• Duration of expression
• Safety

And while there are many different delivery methods in various phases of development for different CGT applications, none is considered as one specific method that could be versatile and used for all of them. Each comes with specific advantages and disadvantages.

Ex Vivo – The Most Mature
Ex vivo CRISPR-based gene editing applications remain the most mature and clinically validated CRISPR applications, particularly for hematologic and immunologic disorders. Electroporation is still the dominant delivery method for ex vivo CRISPR gene editing with major players like MaxCyte, Lonza all having their own high-standard electroporation device on the market.

With this method, cells, typically T cells or Hematopoietic Stem Cells (HSCs) and Inducible Progenitor Stem cells (IPSCs) are briefly exposed to an electrical pulse that allows the specific CRISPR payloads or components to enter the cytoplasm. Electroporation still remains a bit of a gold standard even though the impact on cell viability can be detrimental. Another limitation is its requirement for expensive and sophisticated cell processing equipment and infrastructure.

In Vivo – Opportunities with Challenges
In vivo CRISPR therapies, where gene editing occurs directly inside the patient’s body, represents the greatest opportunity and the greatest challenge in the field. AAV has been the workhorse vector for in vivo gene therapy and was the first to enable in vivo CRISPR gene editing in humans.

However, there are a few limitations, including the limited payload capacity (+/- 4.7 kb) of the viral capsid, pre-existing immunity and re-dosing limitations, and prolonged Cas-nuclease expression, which increases off-target risks. To overcome the size constraints, scientists have developed strategies including smaller Cas proteins, split-Cas systems or dual AAV vectors approach. Even with these challenges, AAV remains a powerful option for tissues such as liver, muscles, and eyes.

Non-viral – Gaining Traction
Non-viral delivery methods have gained more traction over the past years and are considered a viable alternative for viral transfection with in vivo CRISPR therapies. Several approaches are under development globally, including the following:

• Polymer-based nanoparticles that have tunable chemistry and release kinetics, have potency for tissue targeting, but often face challenges with toxicity and consistency
• Cell-penetrating peptides, including direct Cas9 fusion strategies that show promise for localized or topical delivery, but remain largely preclinical
• Physical delivery methods like photoporation based delivery, microinjection, hydrodynamic injection, or localized administration, but such applications remain very niche and often face limited scalability.

The Takeaway
Innovation in CRISPR delivery is accelerating along several fronts:

• Next-generation LNPs with extrahepatic targeting
• Engineered viral capsids with improved specificity and immune evasion
• Smaller and more precise editors (base and prime editors) optimized for delivery constraints
• Combination approaches blending physical, chemical, and biological systems

As CRISPR therapeutics expand into more complex diseases and tissues, delivery will remain the primary differentiator between promising science and commercially viable therapy.

• Have questions on this topic? Contact Us
• Learn more on our Gene Editing pages
• Visit our CRISPR Genome Editing page
• Have an idea for a topic? Let us know!

Subscribe to our blog