Use of high molecular mass pABOLs for nucleic acid delivery

This technology introduces the use of bioreducible polymers to deliver long RNA and DNA molecules for next-generation nucleic acid vaccines targeting infectious diseases and cancer.

Proposed Uses

• RNA and DNA vaccine delivery for infectious diseases and cancer
• Gene therapy applications requiring efficient and safe nucleic acid delivery
• Ex vivo cell engineering for immunotherapy or regenerative medicine
• In vivo therapeutic protein expression via mRNA or saRNA vectors.

Problems addressed

Despite significant advances in nucleic acid therapeutics, several persistent challenges continue to limit the clinical translation of RNA and DNA-based vaccines and therapies:

• DNA vaccines require nuclear entry and risk genome integration, while RNA vaccines (though safer) are unstable and easily degraded. saRNA offers stronger immune responses but is difficult to deliver due to its large size. Also, viral vectors are effective but complex and expensive, whereas current non-viral systems suffer from toxicity and low efficiency. This invention aims to provide a safe, non-viral polymer delivery system capable of efficiently protecting and delivering RNA and DNA, including long saRNA molecules
• Traditional P(ABOL) polymers are limited to ~5 kg/mol, restricting their ability to condense nucleic acids effectively. This invention introduces a modified polyaddition reaction using higher monomer concentration and Lewis base catalysis, enabling rapid, tunable synthesis of high-molecular-weight polymers (8–167 kg/mol). These high-mass polymers are fully degradable and reproducible
• Large saRNA molecules (5–20 kb) are difficult to stabilize using conventional polymers. Low-mass carriers form weak complexes, while high-mass ones like PEI are toxic. The bioreducible poly(amido amine)s described here combine strong condensation (due to higher chain length) with safe intracellular release via disulfide bond reduction.

Technology Overview

This technology introduces a new class of bioreducible poly(amido amine) polymers, [P(CBA-alt-ABOL)x], with tunable high molar mass (8–167 kg/mol), designed for efficient and safe delivery of RNA and DNA therapeutics. Synthesized via a catalysed polyaddition using N,N'-Bis(acryloyl)cystamine (CBA) and 4-amino-1-butanol (ABOL), these polymers form stable nanoparticles that protect nucleic acids from degradation and enable high transfection efficiency, particularly with self-amplifying RNA (saRNA). Compared to polyethyleneimine (PEI), the current gold standard in polycationic delivery, high molar mass P(CBA-alt-ABOL)s demonstrate significantly superior performance: up to 2–3 orders of magnitude higher transfection efficacy with saRNA and approximately one order of magnitude with other RNA and DNA molecules, while exhibiting negligible cytotoxicity. The technology also incorporates a titration-based complexation method for precise control of particle size and surface charge, ensuring compatibility with sterile filtration and GMP manufacturing, making it a promising platform for next-generation nucleic acid vaccines and biotherapeutics.

Development stage

Additional preclinical animal work is ongoing to show that the use of our pABOL provides significant advantages over the use of other delivery formulations as it relates to the magnitude, duration and or functional characteristics of the induce antibody response to formulated RNA vectors.