The landscape of genetic medicines for in vivo T cell reprogramming.

In vivo CAR-T therapy: The shift from ex vivo culturing to direct in situ immune reprogramming.

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.

Tracking therapeutic T cells in vivo.

Transient T cell therapies.

In vivo engineering of CAR immune cells by nonviral nanoparticles.

Nonviral NPs are poised to redefine CAR therapy by enabling scalable, off-the-shelf immune interventions for cancer, autoimmune, and fibrotic diseases.

In-vivo CAR-T Cell Engineering: A Narrative Review of Emerging Delivery Strategies and Their Potential Future Impact on Accessibility

Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a groundbreaking advancement in cancer immunotherapy, progressively improving over decades and producing remarkable clinical outcomes. This review examines the evolution of CAR-T cell therapy by comparing ex vivo and newer in-vivo approaches, evaluating the four primary delivery vehicles used for in-vivo CAR-T therapy, and discussing their implications for safety, scalability, accessibility and future development. Although ex vivo CAR-T therapy has demonstrated substantial clinical success, its complex manufacturing process, high cost, prolonged production time, and reliance on specialized facilities limit patient access worldwide. In contrast, in-vivo CAR-T therapy genetically reprograms T cells directly within the body, eliminating external manipulation of T cells and thus many of the logistical barriers associated with ex vivo manufacturing. Four primary delivery vehicles have shown immense progress within-vivo CAR-T cell therapy: lentiviral vectors, lipid nanoparticles, polymeric nanoparticles, and virus-like particles. Each delivery platform offers distinct advantages and limitations in terms of efficacy, safety, and scalability. Most evidence for in-vivo CAR-T therapy to date comes from preclinical and early-phase studies; if these approaches continue to mature, they may offer a more scalable, cost-effective, and accessible alternative to traditional ex vivo CAR-T therapy, though this remains a projected rather than demonstrated benefit.

Nano meets CAR-T: A new era in cancer immunotherapy.

Chimeric antigen receptor (CAR)-T cell immunotherapy is one of the emerging advancements in personalized treatment of cancer, whose design is based on the genetic modification of T cells to express chimeric antigen receptors (CARs) to generate CAR-T cells, specifically targeting cancer tissues. Despite the fact that immunotherapy provides significant antitumor activity, only a limited number of therapies reached the market after their FDA approval because of the accompanying challenges including tumor resistance, side effects, high cost of production, possible toxicities during CAR-T cells engineering, and poor selectivity. Nanotechnology has emerged as a promising approach for improving drug targeting, selectivity and reducing their side effects. In this context, recent advances highlight the innovative integration of nanomaterials for enhancing CAR-T cell engineering, delivery, and in vivo functionality. Nanotechnology-enabled strategies such as nanoparticle-based gene delivery systems, nanoformulations for controlled CAR expression, and tumor microenvironment modulation have demonstrated significant potential in overcoming current therapeutic limitations. Therefore, substantial research efforts are currently focused on integrating this technology in developing CAR-T cell immunotherapy. This review article focuses on CAR-T cell bioengineering, antitumor mechanism of action, challenges and limitations, as well as the latest innovative nanotechnological solutions for complementing CAR-T cell immunotherapy. It also emphasizes the translational applications and design innovations of nanotechnology, including precision targeting platforms and multifunctional nanocarriers, highlighting that nanotechnology may play an important role in advancing the efficacy, safety, and clinical applicability of personalized CAR-T cancer immunotherapy.