SMART NANPs: new molecular platform for communication with human immune system and modulation of therapeutic responses

首席调查员/项目主任(最后、第一、中间)：阿福宁、基里尔、A 项目总结 如果医疗保健提供者配备了生物兼容、可生物降解、坚固耐用且负担得起的 将治疗方式与受控作用机制相结合的治疗方案？如果这件事 多功能技术具有学习能力，可以接受教育以识别患者特定的疾病和 通过改变基本的细胞过程来干扰它们的进程？如果同样的配方 可以提供另一种控制患者免疫反应的手段，并进一步促进有利的 毒性最小的治疗结果？这些下一代疗法将成为一种游戏 帮助从源头上预防、检测、诊断和治疗疾病和残疾。与 在Mira(R35)资金的支持下，我们设想了一个数据驱动的平台、智能NNP(特定、模块化、 可调节的、可重复的和靶向的核酸纳米颗粒)，由自组装的核酸编码。通过 控制着所有生命形式的遗传信息的流动，核酸已经成为 获得有关主要细胞过程和疾病起源的新知识。除了它们不同的生物学特性 这些生物聚合物可以被编程为具有特定物理化学性质和 决定NANP生物学行为的功能，具有对细胞重新编程的无限可能性 通过分子信号传递的行为。我们最近发现，不同的架构参数和 NANPs的成分被输送到原代人类免疫细胞，可以激活单核细胞和树突状细胞 以产生I型和III型干扰素。这项关于NANP免疫识别的开创性工作突出了 这项技术在疫苗和免疫治疗领域的意外临床应用。一个已定义的 任何给定NANP的结构-功能关系将允许有条件地激活其 通过一套嵌入的建筑代码进行免疫识别或任何其他治疗活动。有了这个 概念，我们引入了治疗性NANP的两个正交概念，这两个概念可以在 人类癌细胞释放预先编程的治疗药物。通过将这些突破和其他 来自我的实验室的初步发现，如当前应用程序中突出显示的，并将它们集成到统一的 智能NANP网络，可对生物分布、免疫活性和治疗进行可编程控制 模块，我们将推进目前针对传染病和癌症的治疗方案(通过 基于NANP的疫苗和免疫疗法)、心血管疾病(通过以下方式调节凝血 凝血酶靶向NANP)，并解决药物过量和安全问题(通过 NANP及其受控失活)。为了最大限度地成功翻译这项技术， 拟议的计划将采用跨越核酸纳米技术领域的多学科方法， 免疫学、药物输送、转化肿瘤学和机器学习。这项计划的长期目标是 将智能NANP提升到临床使用的水平。

Principal Investigator/Program Director (Last, First, Middle): Afonin, Kirill, A PROJECT SUMMARY What if healthcare providers were equipped with biocompatible, biodegradable, robust, and affordable treatment options that combine therapeutic modalities with controlled mechanisms of action? What if this versatile technology had learning capacity and could be educated to recognize patient-specific diseases and interfere with their progression by redirecting fundamental cellular processes? What if the very same formulation could offer an additional means of control over patients’ immune responses and further advance favorable therapeutic outcomes with minimal toxicities? These next generation therapies would then become a game changer in helping to prevent, detect, diagnose, and treat diseases and disabilities at their source. With the support from MIRA (R35) funding, we envision a data-driven platform, SMART NANPs (specific, modular, adjustable, reproducible, and targeted nucleic acid nanoparticles), encoded by self-assembling nucleic acids. By controlling the flow of genetic information across all forms of life, nucleic acids have become instrumental in acquiring new knowledge about major cellular processes and origins of diseases. Besides their diverse biological roles, these biopolymers can be programmed into NANPs with specified physicochemical properties and functionalities that dictate NANPs’ biological actions with endless possibilities for reprogramming cellular behavior through molecular signaling. We recently discovered that different architectural parameters and compositions of NANPs, delivered to primary human immune cells, can activate monocytes and dendritic cells to produce type I and type III interferons. This pioneering work on NANPs’ immunorecognition highlighted an unforeseen clinical application for this technology in the field of vaccines and immunotherapy. A defined structure-function relationship for any given NANP would then allow conditional actuation of its immunorecognition or any other therapeutic activity through a set of embedded architectural codes. With this notion, we introduced two orthogonal concepts of therapeutic NANPs which can be conditionally activated in human cancer cells to release pre-programmed therapeutics. By uniting these breakthroughs and other preliminary findings from my lab, as highlighted in the current application, and integrating them into a unified network of SMART NANPs with programmable control of biodistribution, immunological activity, and therapeutic modules, we will advance the current repertoire of therapies against infectious diseases and cancers (through NANP-based vaccines and immunotherapies), cardiovascular diseases (through regulated coagulation by thrombin-targeting NANPs), and address drug overdose and safety issues (through the biodegradable nature of NANPs and their controlled deactivation). To maximize the successful translation of this technology, the proposed program will employ a multidisciplinary approach that spans the fields of nucleic acid nanotechnology, immunology, drug delivery, translational oncology, and machine learning. The long-term goal of this program is to elevate SMART NANPs to the level of clinical use.