We developed a genome-wide CRISPR activation screen in CAR-T cells to identify genes that enhance survival and proliferation under inhibitory conditions. The screens successfully identified known positive and negative regulators and, importantly, highlighted novel candidates. Further, we developed tumor microenvironment remodeling strategies to amplify and diversify the antitumor immune response against solid tumors.

CREATE Medicines develops mRNA-based immunotherapies to directly program immune cells in vivo thereby eliminating complex ex vivo manufacturing and reduced time to treatment. Cell-specific CAR mRNA products delivered through lipid nanoparticles, enable us to launch a multi-immune cell attack on cancer or autoreactive cells. Preclinical studies in mice and non-human primates highlight the potential of a multi-pronged in vivo cell therapy to drive stronger and longer-lasting outcomes for patients.

Targeted delivery of RNA-based therapeutics for in vivo cellular reprogramming holds significant potential. In this talk, I will explain how we can selectively target mRNA therapeutics to specific cells and cell subtypes using antibody-modified lipid nanoparticles. Additionally, I will discuss the recent potential applications we’ve explored with this platform technology.

CAR T cell therapy has set a new benchmark in patients with certain hematologic malignancies, but significant barriers to patient access remain. In this talk we will present the design and characterization of an LNP system designed to reprogram T cells in vivo. This system can specifically transfect T cells with an active CAR in vitro and in vivo and has the potential to revolutionize patient access to cell therapies.

Extrahepatic targeting for genetics medicines remains a key challenge. Mirai Bio has built an open platform driven by machine intelligence and in vivo barcoding to develop next-generation ionizable lipids and formulations. These base LNPs can be tuned for high on-target delivery to chosen cell types and favorable off-target selectivity, specifically reduced liver delivery. Further increases in potency and selectivity are seen through the addition of targeting moieties to the surface.

• Discuss key platform design principles including T cell targeting control of CAR expression and modulation of immune activity 
• Highlight how advances in targeting and payload engineering aim to improve specificity durability and safety 
• Explore the implications of scalable redosable in vivo CAR T approaches for future cell therapy development and clinical translation​

Highly effective, yet complex to manufacture, simplifying CAR T cell generation is at the forefront of current research. The recent progress in generating CAR T cells directly in the patient relies heavily on vector technology, particularly high selectivity for T lymphocytes. This presentation will discuss different vector platforms focusing especially on engineering strategies for lentiviral vectors, AAV vectors and lipid nanoparticles displaying DARPins recognizing T cell marker as entry receptor.

Here we demonstrate that stable and cell-specific transgene expression can be achieved through in vivo site-specific integration of large DNA payloads. We developed a two-vector system to deliver CRISPR-Cas9 and DNA template. We optimized both vectors for specificity of delivery to T cells and knock-in efficiency. By integrating a CAR transgene into a T cell-specific locus we generated in vivo therapeutic levels of CAR T cells in hematological and solid malignancies.

Targeted delivery of lipid nanoparticles (LNPs) using protein-based strategies presents a promising opportunity to broaden the clinical application of RNA therapeutics. Conjugation strategies enable the decoration of LNPs with antibodies or antibody fragments; however, scalable production remains a significant challenge. In this study, we evaluated the integration of a synthetically engineered peptide tag-lipid into LNPs, alongside an ApoE2-tag design that facilitates rapid antibody conjugation while preserving particle integrity during storage and large-scale production.

In vivo generation of CAR T cells using mRNA-loaded LNPs represents a scalable alternative to ex vivo cell therapies, but clinical translation has been limited by transient expression, suboptimal potency, and safety concerns. We present a CD8-targeted, T-cell-restricted mRNA-LNP platform that integrates AI-engineered binding domains for both nanoparticle decoration and CAR antigen recognition, enabling controlled, titratable, and localized cytokine armouring. Preclinical studies demonstrate enhanced lineage specificity, improved functional persistence, and favourable tolerability profiles, with compatibility for reduced-frequency redosing. Data from murine and non-human primate models support the translational potential of this approach for repeat-dose, in vivo CAR T cell therapies.

One of the hurdles of mRNA technologies is to achieve sufficient therapeutic payload. Higher dosages often have increasing toxicities while lower dosages are difficult to reach the therapeutic threshold, even with frequent dosage. To address this hurdle, we developed a CATP system, co-delivering self-amplifying mRNA (SamRNA) and modified mRNA encoding alphavirus capsids and envelopes. The CATP system initiates a dual-amplification process: SamRNA amplifies therapeutic payloads within transfected cells, while capsid and envelope proteins package SamRNA into defective viral particles to infect neighboring cells, enabling secondary payload amplification and offering new opportunities for overcoming payload limitations across diverse malignancies.

Delivering cytokine signals to engineered T cells expands them to therapeutic levels, but systemic cytokines or constitutive signaling cause toxicities. Tools for safely expanding CAR T cells using small molecule-inducible systems are lacking. We developed modular synthetic cytokine receptor platforms delivering cytokine signals (gamma chain cytokines and others) via an FDA-approved small molecule. CAR T cells expressing these receptors demonstrate enhanced expansion, persistence, and anti-tumor efficacy in difficult-to-treat tumor models in vivo.

Adeno-associated virus (AAV)-based donors for genome engineering face safety, manufacturing, and size limitations. At Full Circles, we developed C4DNA, a non-viral genome writing platform producing mini-circular single-stranded DNAs up to ~20 kb for precise, efficient transgene integration. C4DNA platform achieves up to 70% knock-in efficiency in iPSCs and enable robust editing across primary immune cells using diverse nuclease systems. In CAR T and NK cells, C4DNA demonstrates superior precision, safety, and scalability, overcoming key challenges of dsDNA and lssDNA donors. This technology establishes a new foundation for next-generation non-viral immune cell therapies in oncology and autoimmune diseases.