CRISPR is administered in two fundamentally different ways: outside the body (ex vivo), where cells are removed, edited in a lab, and returned to the patient, or inside the body (in vivo), where editing components are delivered directly through an IV infusion or injection. The method depends on which cells need editing and how accessible they are. As of 2025, the only FDA-approved CRISPR therapy, Casgevy, uses the ex vivo approach, but in vivo treatments delivered by IV are advancing rapidly through clinical trials.
Ex Vivo: Editing Cells Outside the Body
The ex vivo method is the most established approach and the one used in the first CRISPR therapy ever approved. It works best for blood disorders because blood stem cells can be removed, edited, and transplanted back relatively easily. Casgevy, approved in December 2023 for sickle cell disease and transfusion-dependent beta thalassemia, follows this model.
The process has several stages. First, a patient’s blood stem cells are collected from the bone marrow. Those cells go to a specialized lab, where the CRISPR machinery edits a specific gene. In Casgevy’s case, the edit boosts production of fetal hemoglobin, a form of hemoglobin that compensates for the defective version causing sickle cell disease. Lab technicians verify the edits before the cells are cleared for transplant.
While the cells are being prepared, the patient undergoes myeloablative conditioning, which is high-dose chemotherapy designed to clear out the existing bone marrow. This makes room for the edited stem cells to take hold once they’re infused back in. Patients are typically admitted to a transplant unit for at least one month to cover the conditioning, the single-dose infusion of edited cells, and the initial recovery period. The edited stem cells then engraft in the bone marrow, attaching and multiplying to produce healthy blood cells going forward.
This is a one-time treatment, not something repeated. But the chemotherapy component is intense, carrying its own risks including infection, fatigue, and fertility effects. It’s the main reason ex vivo CRISPR therapy remains a serious medical undertaking rather than a routine procedure.
In Vivo: Delivering CRISPR Directly Into the Body
For organs you can’t easily remove and edit in a dish, like the liver, CRISPR components need to travel through the bloodstream and reach the right tissue. This is in vivo editing, and the leading delivery vehicle is the lipid nanoparticle, or LNP. These are tiny fat-based spheres, similar in concept to the delivery system used in mRNA COVID vaccines, that protect the fragile CRISPR components and shuttle them into cells.
When lipid nanoparticles are injected into the bloodstream, they naturally accumulate in the liver. This happens for two reasons: the liver has an enormous blood supply with specialized blood vessels that allow particles to pass through, and proteins in the blood coat the nanoparticles in a way that liver cells readily absorb them. This makes the liver the easiest organ to target with this approach.
The most advanced in vivo CRISPR program targets a condition called transthyretin amyloidosis, where a misfolded protein produced by the liver builds up and damages the heart and nerves. In clinical trials, single IV infusions at doses of 0.7 or 1.0 mg/kg of body weight successfully reduced production of the problem protein. The treatment, called NTLA-2001, is administered as a straightforward intravenous drip.
In a striking case in 2025, a personalized in vivo CRISPR therapy was developed for an infant named KJ with a rare liver enzyme deficiency called CPS1 deficiency. The treatment was designed, approved by the FDA, and delivered within just six months, all via IV infusion using lipid nanoparticles. This demonstrated that in vivo CRISPR delivery could work not just in trials but as a rapid-response therapeutic tool.
Direct Injection for Specific Organs
Some tissues can’t be reached effectively through the bloodstream. The eye is one example. For retinal diseases, CRISPR components are packaged inside viral vectors, typically adeno-associated viruses (AAVs), which are harmless viruses engineered to carry genetic cargo instead of their own DNA. These are injected directly beneath the retina in a surgical procedure, placing the editing tools right next to the cells that need correction.
This subretinal injection approach is being tested for inherited forms of blindness and conditions involving abnormal blood vessel growth in the eye. The volumes are tiny and the procedure is precise, performed under a surgical microscope. Viral vectors work well here because the eye is a small, enclosed space that needs relatively few particles to treat, and it’s partially shielded from the immune system, reducing the chance of an inflammatory reaction.
How CRISPR Gets Into Individual Cells
Regardless of how CRISPR reaches the right tissue, it still has to cross cell membranes and enter the nucleus where DNA lives. The method depends on whether cells are being edited in a lab dish or inside the body.
For ex vivo therapies, the most common technique is electroporation. This uses brief electrical pulses to temporarily open tiny pores in cell membranes, allowing CRISPR components to slip inside. It’s performed using specialized devices in the lab, not in the patient. The electrical parameters have to be carefully calibrated because too much voltage damages cells and too little doesn’t open the pores enough.
For in vivo therapies, the delivery vehicle itself handles cell entry. Lipid nanoparticles fuse with cell membranes (since both are made of fat), releasing their contents inside. Viral vectors bind to specific receptors on cell surfaces and are pulled inside through the cell’s natural uptake processes.
What Form CRISPR Takes When Delivered
CRISPR can be packaged in three forms, and each has different tradeoffs for safety and speed.
- DNA (plasmids or viral vectors): The cell reads the DNA instructions and builds the CRISPR protein itself. This lasts the longest inside cells, which is useful in some contexts but raises the risk of the DNA accidentally inserting into the patient’s own genome and disrupting important genes.
- mRNA: The cell translates the mRNA into the CRISPR protein without any DNA integration risk. However, mRNA is fragile and depends on the cell’s own protein-building machinery, which limits efficiency.
- Ribonucleoprotein (RNP): The CRISPR protein and its guide RNA are pre-assembled and delivered as a ready-to-go complex. RNPs start cutting target DNA almost immediately, reach peak activity within 24 hours, and degrade within 24 to 48 hours. This rapid in-and-out action gives them the lowest off-target editing rates and the least cellular toxicity of the three formats.
RNP delivery is preferred for ex vivo therapies where electroporation can get the complex directly into cells. For in vivo therapies delivered by lipid nanoparticles, mRNA is more commonly used because it packages more efficiently inside the particles.
What the Patient Actually Experiences
The patient experience varies dramatically depending on the approach. For ex vivo therapies like Casgevy, the process resembles a bone marrow transplant. You undergo stem cell collection (which may involve injections to mobilize stem cells into the blood over several days), then weeks of waiting while cells are edited, then intensive chemotherapy, and finally the infusion itself followed by weeks of monitored recovery in a hospital transplant unit. The total timeline from collection to discharge stretches across months.
For in vivo therapies, the experience is far simpler. An IV infusion of lipid nanoparticles takes hours, not months, and can be done without chemotherapy or extended hospitalization. This is one reason researchers are working hard to expand in vivo delivery to more organs beyond the liver. If CRISPR can be delivered by a single infusion rather than a full transplant protocol, it becomes accessible to far more patients.
Direct injections to the eye or other specific tissues fall somewhere in between. They require a surgical procedure, but it’s typically outpatient with a short recovery window rather than a month-long hospital stay.