Nonviral NPs are poised to redefine CAR therapy by enabling scalable, off-the-shelf immune interventions for cancer, autoimmune, and fibrotic diseases.
Abstract
Chimeric antigen receptor (CAR) immune cell therapy has revolutionized the treatment of hematologic malignancies, yet conventional ex vivo manufacturing remains costly, complex, and logistically demanding. Emerging in vivo engineering strategies, especially those based on nonviral nanoparticles (NPs), offer a transformative alternative by enabling direct programming of immune cells within the body. Recent advances in NPs-mediated delivery of CAR constructs, including mRNA, circular RNA (circRNA), self-amplifying RNA (saRNA), DNA and gene editing tools, have demonstrated promising potential for achieving transient, tunable and repeatable expression with reduced genotoxicity. Immune cell targeting has been achieved by multiple targeting strategies for T cells, NK cells and macrophages, allowing precise control of CAR expression and functional activation in disease-relevant contexts. For T cells specifically, antibody-functionalized NPs categorized by antibody types including CD3, CD4, CD5, CD7 and CD8, demonstrate differential engagement of T cell subsets and influence their activation profiles across various therapeutic contexts. This review highlights key advances in the development of immune cell targeting NPs, discusses evolving CAR architectures and quality control considerations, and outlines future directions for integrating in vivo CAR platforms into broader immunotherapeutic landscapes. Nonviral NPs are poised to redefine CAR therapy by enabling scalable, off-the-shelf immune interventions for cancer, autoimmune, and fibrotic diseases.
The intrinsic trade-off between therapeutic durability and biosafety across distinct delivery platforms is discussed, along with the necessity that their clinical translation hinges on systematic optimization of delivery precision, immune compatibility, and expression controllability.
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This review highlights key engineering strategies enabling in vivo CAR T-cell generation, summarizes emerging clinical research and development, and discusses future opportunities for expanding in vivo CAR T-cell therapies as scalable immunotherapy platforms.
Janani Gopalakrishnan, B. Rathod, Sachin Puri· International Immunopharmaco...· 0 citations
The pharmacological imperative for transient CAR expression is delineated, including lipid nanoparticles in combination with mRNA, which avoids risks of insertional mutagenesis and enables titratable, short-lived CAR expression, thereby enhancing safety management and suitability for applications beyond oncology.
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This review aims to provide actionable guidance to bench-side cell engineering to broad clinical applications by comprehensively discussing recent advancements in LNP formulation and next-generation RNA payload engineering.
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The integration of rational material design, high-throughput screening, artificial intelligence, and interdisciplinary collaboration will be essential to advance next-generation targeted in vivo mRNA cell therapies toward clinical translation.
Danyang Wang, Yumin Li, Jinfeng Deng et al.· Drug Delivery· 0 citations
Ex vivo-manufactured chimeric antigen receptor (CAR) T cells targeting CD19 have transformed treatment strategies for patients with B cell malignancies and shown promising results in autoimmune disease. Yet despite their success, significant barriers remain that impede patient access to these therapies, including their complex manufacturing and the need for lymphodepleting chemotherapy. Moreover, many patients who receive ex vivo-manufactured CD19 CAR T cells do not achieve durable responses, suggesting that the expansion and persistence of CAR T cells may need improvement, and/or that strategies targeting alternative antigens may be needed for patients who are refractory to or relapse following treatment with CD19-directed therapies. Umoja is developing a surface-engineered lentiviral vector (LVV) platform capable of generating CAR T cells in vivo without lymphodepletion. UB-VV400 delivers a payload comprised of a fully human anti-CD22 CAR and the rapamycin-activated cytokine receptor (RACR), which enable preferential expansion and enrichment of CAR T cells in response to rapamycin. Here, we describe preclinical studies demonstrating that UB-VV400 generates anti-CD22 CAR T cells that kill CD22-expressing B cells and tumor cells in vitro and in vivo, and that engagement of RACR results in the selective expansion and enrichment of CAR T cells in vivo leading to complete tumor clearance and B cell depletion.
Travis J. Friesen, Alyssa Sheih, Nikole Perdue et al.· Molecular Therapy· 0 citations
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