A study published this week in Science Translational Medicine describes a new approach to generating chimeric antigen receptor (CAR) immune cells inside the body, bypassing the expensive and time-consuming ex vivo manufacturing process that currently limits CAR cell therapy. Rather than targeting T cells, the researchers used red blood cells as couriers to deliver mRNA directly to myeloid cells in the spleen, generating functional CAR myeloid cells in living mice that migrated to tumors and reshaped the immune environment.
The Finding
Nie et al. developed a platform called mRNA-LNP-Ery, in which mRNA-loaded lipid nanoparticles (LNPs) are covalently anchored onto the surface of erythrocytes (red blood cells). The key insight is that red blood cells naturally home to the spleen, where they are phagocytosed by resident myeloid cells as part of normal erythrocyte recycling. The researchers exploited this biology to route mRNA-loaded nanoparticles selectively to CD11b+ myeloid cells in the spleen, achieving efficient delivery with minimal uptake by hepatocytes (the liver cells that normally capture most intravenously injected nanoparticles).
Once inside the myeloid cells, the mRNA was translated into functional CAR proteins. The team tested two CARs: one targeting HER2, a receptor overexpressed in several solid tumors including breast and gastric cancer, and one targeting CD19, the B cell marker targeted in hematological malignancies.
The resulting CAR myeloid cells adopted a proinflammatory, antigen-presenting phenotype. They migrated to tumor sites, directly eliminated cancer cells, and remodeled the tumor microenvironment in ways that increased the infiltration of effector T cells and natural killer (NK) cells. In mouse tumor models, the treatment reduced tumor progression.
Why It Matters
Standard CAR-T cell therapy is among the most effective treatments available for certain blood cancers, but manufacturing it is a practical barrier to broader use. Collecting a patient’s T cells, genetically modifying them in a clean room facility, expanding them, quality testing, and re-infusing them takes several weeks and costs hundreds of thousands of dollars per patient. For patients with rapidly progressing disease, the timeline alone is a problem.
In vivo CAR generation, which reprograms immune cells inside the patient rather than in a manufacturing facility, could change that calculus significantly. Several groups have pursued in vivo CAR-T cell strategies, including a Nature study from earlier this month that also described in-body engineering of CAR immune cells. This new paper takes a different approach by focusing on myeloid cells rather than T cells.
Myeloid cells offer a different set of properties as CAR effectors. T cells, the current standard, often struggle to penetrate solid tumors, which use multiple mechanisms to exclude, exhaust, and suppress cytotoxic T cells. Macrophages and other myeloid cells infiltrate solid tumors more readily, reside within the tumor microenvironment as resident cells, and can present antigens to recruit additional T cell responses. Whether these properties translate to meaningful clinical advantages is an open question, but the biological rationale for myeloid-based CAR approaches is solid.
The erythrocyte delivery mechanism is also notable independent of the CAR application. The specificity for splenic myeloid cells over liver cells is a meaningful advance in LNP targeting. Most lipid nanoparticle formulations accumulate heavily in the liver after intravenous injection. Using red blood cells as a splenic delivery vehicle is an elegant exploitation of existing physiology.
How They Did It
The study used mouse tumor models of colorectal cancer and melanoma. The mRNA-LNP-Ery platform was constructed by covalently attaching mRNA-loaded LNPs to the surface of donor erythrocytes. After intravenous injection, the erythrocytes trafficked to the spleen and were taken up by CD11b+ resident myeloid cells, delivering the CAR-encoding mRNA.
The researchers characterized the phenotype of the resulting CAR myeloid cells, tracked their migration to tumor sites, and assessed antitumor efficacy through tumor volume measurements and survival data. They also performed immune profiling of tumors to confirm the observed increases in T and NK cell infiltration.
The paper’s scope is preclinical. All data shown are from mouse models.
Limitations and Caveats
This is early-stage mouse data. Several important questions remain before this platform could move toward clinical testing.
The CAR expression driven by mRNA will be transient. Unlike viral gene delivery, mRNA is not integrated into the genome and is degraded over time. Whether this transient CAR expression is sufficient for durable antitumor responses in patients, or whether repeated dosing is needed, is not yet known.
The immunogenicity of the mRNA-LNP-Ery construct in a clinical setting also needs evaluation. Erythrocytes themselves are immunologically inert, but the LNP chemistry and the CAR proteins being expressed could provoke immune responses over time.
Mouse tumor models are notoriously poor predictors of clinical outcomes in immunotherapy. The tumor microenvironments of commonly used mouse models differ substantially from human cancers. Results will need to be reproduced in humanized models and eventually in patients before the platform’s clinical promise can be assessed.
The specificity of delivery to myeloid cells, rather than other splenic cell types, was demonstrated but the mechanism of selectivity requires further characterization.
What This Means in Practice
This paper is a proof of concept, not a clinical result. The platform will need to progress through extensive preclinical development, safety studies, and eventually clinical trials before it is relevant to patient care. Given the pace of the in vivo CAR field, this could happen relatively quickly if early safety data are clean, but it remains years away from clinical use.
For researchers working in immunotherapy, LNP delivery, or myeloid cell biology, this paper is worth reading in full. The erythrocyte routing mechanism is a genuinely novel delivery strategy with potential applications beyond CAR cells.
For the broader life science community, this paper is another signal that in vivo immune cell engineering is becoming a competitive and rapidly advancing research area. Multiple groups are now publishing distinct approaches to reprogramming immune cells without ex vivo manufacturing. The tumor microenvironment biology underlying these approaches is becoming central to understanding which patients and which tumor types are most likely to respond.
Source
Nie et al., “In vivo generation of CAR myeloid cells through erythrocyte-mediated mRNA delivery for cancer immunotherapy,” Science Translational Medicine, 2026. DOI: 10.1126/scitranslmed.ady6730