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

基于RNA的药物和疫苗对英国国民健康和财富的重要性与日俱增。这些疗法在低剂量水平下是有效的。不同的疾病可以用不同的RNA治疗；但是，不同的RNA可能是由相同的过程制造的。RNA在患者的细胞内执行其治疗任务：目前，细胞内的递送是通过将RNA掺入脂质纳米粒(LNPs)实现的。然而，由于高脂成本和专利限制，LNP的应用具有挑战性：在LNP制造中使用溶剂(然后去除)；LNP制造和患者之间昂贵的冷链。我们开发了一种新的递送系统，它使用安全和可获得的小分子组件，与CB[8]和RNA自发自组装。这些超分子RNA疗法(SMRT)有效地包裹RNA并将其输送到细胞内，不需要有机溶剂，具有低材料成本(&lt；GB 2/剂量)、良好的室温稳定性，并避免了基于聚合物的RNA输送系统的毒性。SMRT可适应不同的RNA类型，并可配制成包括特殊的稳定或细胞靶向成分，从而有可能治疗身体不同部位的疾病。我们的创新将结合SMRT配方和开发基于流动的微型制造单元，达到适合医院应用的规模。该设施(目前的目标是每天生产数百万剂RNA疫苗)使用模块化的连续流动过程，这允许规模独立(低至单个RNA治疗剂量)。这些方法已经证明了在单一单元中原位制造高浓度的高纯度信使核糖核酸，并将其配制成递送系统。将多核糖核酸合成与SMRT配方相结合，可以简化同一设施的多种药物产品的生产。易于扩展，只需最少的调整即可实现更长的运行时间，而连续的流程验证流程降低了验证复杂性并简化了监管报告，从而缩短了审批时间表和上市时间。占地面积小的单位可以设在个别医院，使RNA药物能够为个别患者或分层患者群体进行本地生产，消除了寒冷和供应链障碍。将针对三阴性乳腺癌(TNBC)的临床实例开发递送系统/制造单元组合。在英国，51%的癌症诊断是乳腺癌(BC)，死亡率为7%。与其他BC相比，TNBC的生长和扩散速度更快，治疗选择更少，复发更多，结果更差，因此需要新的治疗方案。BC是NHS(和全球)的优先事项。项目合作伙伴英国中小企业Aqdot和Centilion Technology以及诺丁汉大学的制药和医学研究小组将超分子组装、基于流动的制造和癌症治疗交付/设计/测试方面的专业知识结合在一起。

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.