Chemistry has been crucial in imparting drug-like properties to oligonucleotides and enabling drug approvals. To further improve oligonucleotide-based therapeutics, we examined spatial architectures that bring the 3'- and 5'-ends together to form transient cyclic structures. We have studied various cyclic structures, including those that linearize upon hybridization with the target RNA or by endogenous factors such as RNase H. These architectures show increased potency and specificity as antisense agents and have broad applicability in developing oligonucleotide-based therapeutics.

Minor structural differences in self and nonself nucleic acids enable viral RNA detection through Toll-Like Receptors 7 and 8 (TLR7/8) and DNA detection through TLR9. Agonists for these receptors have shown separate efficacy as vaccine adjuvants and cancer immunotherapies, yet have not previously been combined into a single therapeutic. We have now developed Z-007, a first-in-class synthetic RNA/DNA TLR7/8/9 agonist that induces very high IFN-a secretion in the absence of an inflammatory response. Z-007 reprograms human tumor-associated immune cells and shows anti-tumor activity following IV administration in mouse liver metastasis models and in pet dogs with spontaneous tumors.

CAR T cell therapy has transformed cancer treatment but remains constrained by the complexity, time, cost, and infrastructure required for ex vivo cell manufacturing. In vivo CAR T offers a potentially transformative alternative by delivering genetic cargo directly to immune cells within the patient, eliminating the need for cell collection, engineering, expansion, and reinfusion. We will explore emerging approaches to in vivo CAR T, discuss the key scientific and translational challenges—including cell targeting, gene expression, safety, durability, and manufacturability—and consider how in vivo CAR T could expand the reach of programmable immune cell therapies.

Following clinical proof-of-concept with first-generation in vivo CAR T, the field is advancing to refined delivery and payload architectures. Next-generation LNPs improve target cell transfection and biodistribution and reduce immunogenicity. New targeting moieties enhance receptor-mediated selectivity, and new CAR targets expand in vivo indications. Optimized mRNA constructs and complex cargoes yield higher, durable, strategically regulated CAR expression from single administrations. Together, advances broaden the therapeutic index and improve clinical applicability.

In vivo CAR T cell therapy using targeted mRNA/LNPs offers a scalable alternative to ex vivo approaches. Across murine and non-human primate models, a novel immunotropic, liver-sparing LNP platform enabled efficient lymphocyte targeting and potent B-cell depletion in blood and lymphoid tissues at low doses, with minimal hepatic transfection and favorable tolerability. These findings support the clinical translation of this platform for B-cell depletion and future expansion to other applications.

In vivo engineered mRNA-based CAR T therapies have the potential to overcome key limitations of conventional viral vector-based approaches through scalable manufacturing, lower cost, redosability, and improved safety. We present a programmable circRNA-tLNP platform for in vivo CAR T cell generation in autoimmune disorders and hematologic malignancies. By optimizing the circRNA backbone, CAR architecture, and targeted LNP delivery, and incorporating miRNA-responsive regulatory elements to enhance specificity, we achieved improved efficacy and safety in preclinical models, highlighting the promise of RNA-based in vivo cell therapies.

Truncating variants in TTN (TTNtv) are the leading genetic cause of dilated cardiomyopathy, with ~40% caused by pathogenic nonsense mutations. Existing treatments try to manage heart failure symptomology without correcting the underlying genetic problem. Tevard Therapeutics is developing suppressor tRNAs that readthrough pathogenic nonsense mutations to restore full-length, functional titin protein. By targeting the genetic cause, this approach offers a disease-modifying strategy for a DCM population with substantial unmet need.

Premature termination codons (PTCs) account for approximately 10% of all genetic disease diagnoses across thousands of rare and ultra-rare conditions. Alltrna is pioneering a novel therapeutic approach using engineered transfer RNA (tRNA) medicines that read through PTCs to restore functional full-length protein production. AP003 is a clinical-stage, liver-directed therapy with nonclinical data showing dose-dependent protein rescue and disease biomarker lowering in multiple models, supporting development across inborn errors of metabolism.

Targeted mRNA therapeutics offer a powerful strategy for treating cardiovascular disease by enabling transient, non-integrating, and cell-specific expression of therapeutic proteins in the heart. Our work focuses on engineering modified mRNA and cell-specific translation platforms using LNP to promote cardiomyocyte proliferation, survival, angiogenesis, and cardiac regeneration while reducing fibrosis and adverse remodeling, thereby advancing precise and controllable mRNA-based therapies for myocardial infarction and heart failure.

Short-acting mRNA and short-acting peptide biology share the same ceiling: expression measured in hours to days, forcing frequent dosing. ScionxBio's xRNA platform expands RNA chemistry beyond its natural four-letter alphabet, engineering molecules with dramatically extended stability and expression duration, validated across multiple protein targets in mice and non-human primates. We'll share platform data and discuss the chemistry and screening approach behind this durability profile.