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越来越重要。这些治疗剂在低剂量水平下有效。不同的疾病可以用不同的RNA治疗;但是不同的RNA可以通过相同的过程产生。RNA在患者的细胞内执行其治疗任务：细胞内递送目前通过将RNA掺入脂质纳米颗粒（LNP）来实现。然而，由于高脂质成本和专利限制，LNP的使用具有挑战性：LNP制造中的溶剂使用（然后去除）;以及LNP制造和患者之间昂贵的冷链。我们已经开发了一种新的递送系统，该系统使用安全且可获得的小分子组分，其与CB\[8\]和RNA自发自组装。这些超分子RNA治疗剂（SMRT）有效地封装RNA并将其递送到细胞中，不需要有机溶剂，具有低材料成本（<£2/剂量），良好的室温稳定性，并且避免了基于聚合物的RNA递送系统的毒性。SMRT可适应不同的RNA类型，并可配制成包含特殊稳定或细胞靶向成分的制剂，从而有可能解决身体不同部位的疾病。我们的创新将联合收割机SMRT制剂与基于流动的制造单元的开发相结合，以达到适合医院应用的规模。该设施（目前旨在每天生产数百万剂RNA疫苗）使用模块化连续流工艺，允许规模独立性（低至单个RNA治疗剂量）。该方法已经证明了在高浓度下在单个单元中原位制造高纯度mRNA并将其配制成递送系统。将多RNA合成与SMRT制剂相结合，可以在同一设施中简化多种药物产品的生产。易于扩展，可在最小调整的情况下延长运行时间，而连续流程验证可降低验证复杂性并简化监管报告，从而缩短批准时间表和上市时间。小占地面积的单元可以位于各个医院，使RNA药物的本地生产能够用于个体患者或分层患者群体，消除冷链和供应链障碍。交付系统/制造单元组合将针对三阴性乳腺癌（TNBC）的临床实例进行开发。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往往生长和传播得更快，治疗选择更少，复发率更高，更糟糕outcomes.so需要新的治疗选择。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Centistry Technology以及诺丁汉大学的药学和医学研究小组联合收割机结合了超分子组装，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。

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.