Supramolecular RNA therapeutics (SMRTs) - developing tunable formulations with scale-independent manufacture.

RNA-based medicines and vaccines are of increasing importance to UK national health and wealth. These therapeutics are effective at low dose levels. Different diseases can be treated with different RNAs; but Different RNAs, however, may be made by the same process.

The RNA performs its therapeutic task inside a patient's cells: intracellular delivery is currently achieved by incorporating RNA into Lipid Nanoparticles (LNPs). However, LNP use is challenging because of high lipid cost and patent constraints: solvent use (then removal) in LNP manufacture; and expensive cold chain between LNP manufacture and patient.

We have developed a new delivery system that uses safe and accessible small-molecule components which, with CB\[8\] and RNA, spontaneously self-assemble. These supramolecular RNA therapeutics (SMRTs) efficiently encapsulate and deliver RNA into cells, do not require organic solvents, have low material costs (<£2/dose), good room-temperature stability, and avoid the toxicity of polymer-based RNA-delivery systems. SMRTs are adaptable to different RNA types and may be formulated to include special stabilising or cell-targeting components, giving potential to address diseases in different parts of the body.

Our innovation will combine SMRT formulations with development of a miniaturised flow-based manufacture unit to a scale suitable for in-hospital applications. The facility (currently aimed at producing millions of doses of RNA-vaccine/day) uses modular continuous-flow processes, which permits scale independence (down to individual RNA-therapeutic doses). The processes have already demonstrated in-situ in a single unit manufacture of high-purity mRNA at high concentration _and_ formulation into a delivery system. Integrating multi-RNA synthesis with SMRT formulation enables streamlined production of multiple drug products from the same facility. Ease in scaling enables longer running with minimal adjustments, while continuous process-verification-in-flow reduces validation complexity and simplifies regulatory reporting, yielding shorter approval schedules and time-to-market. Small-footprint units can be sited in individual hospitals, enabling local production of RNA-medicine for individual patients or stratified patient groups, eliminating cold- and supply-chain hurdles.

The delivery-system/manufacturing-unit combination will be developed for the clinical example of triple negative breast cancer (TNBC). In the UK, 51% of cancer diagnoses are for breast cancer (BC), which has 7% mortality. Compared to other BCs, TNBC tends to grow and spread faster, have fewer treatment options, more recurrences, and worse outcomes.so needs new therapeutic options. BC is an NHS (and global) priority.

Project partners UK SMEs Aqdot and Centillion Technology and Nottingham University's research groups in Pharmacy and Medicine combine expertise in supramolecular-assembly, flow-based manufacture, and cancer therapy delivery/design/testing.