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的健康和财富越来越重要。这些疗法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在患者细胞内执行其治疗任务：目前通过将RNA结合到脂质纳米颗粒（LNPs）中来实现细胞内递送。然而，LNP的使用具有挑战性，因为高脂成本和专利限制：在LNP制造中使用溶剂（然后去除）；以及LNP制造商和患者之间昂贵的冷链。我们开发了一种新的递送系统，该系统使用安全且易于获取的小分子成分，这些成分与CB \[8\]和RNA一起自发自组装。这些超分子RNA疗法（SMRTs）有效地将RNA包裹并递送到细胞中，不需要有机溶剂，材料成本低（< 2英镑/剂），室温稳定性好，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。我们的创新将把SMRT配方与小型流动制造装置的开发结合起来，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）使用模块化连续流程，允许规模独立性（降低到单个rna治疗剂量）。该工艺已经在单个单元中原位证明了高浓度高纯度mRNA的制造，并将其配制成递送系统。将多rna合成与SMRT配方集成，可以从同一设施简化多种药物产品的生产。易于扩展，只需最小的调整即可延长运行时间，而连续的流程验证降低了验证的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。占地面积小的设备可以安置在各个医院，从而能够在当地为个别患者或分层患者群体生产rna药物，从而消除冷链和供应链障碍。将针对三阴性乳腺癌（TNBC）的临床实例开发输送系统/制造单元组合。在英国，是51岁% 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.

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.