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

SMART NANP：与人体免疫系统通讯和调节治疗反应的新分子平台

• 批准号: 10331771
• 负责人: Kirill A Afonin
• 金额: $ 38.52万
• 依托单位: UNIVERSITY OF NORTH CAROLINA CHARLOTTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10331771
• 关键词: Address; Architecture; Biodistribution; Biological; Biopolymers; Cardiovascular Diseases; Cell physiology; Cells; Clinical; Coagulation Process; Code; Communicable Diseases; Communication; Data; Dendritic Cells; Diagnosis; Disease; Drug Delivery Systems; Formulation; Funding; Goals; Health Personnel; Human; Immune; Immune response; Immune system; Immunization; Immunologics; Immunology; Immunotherapy; Interferons; Knowledge; Learning; Life; Machine Learning; Malignant Neoplasms; Modality; Molecular; Nanotechnology; Nature; Nucleic Acids; Overdose; Pathway interactions; Patients; Pharmaceutical Preparations; Principal Investigator; Property; Public Health; Regulation; Reproducibility; Research; Role; Safety; Signal Transduction; Source; Specific qualifier value; Structure-Activity Relationship; Technology; Therapeutic; Thrombin; Toxic effect; Translations; Vaccines; Work; base; biomaterial compatibility; cancer cell; cell behavior; clinical application; disability; genetic information; immunoregulation; interdisciplinary approach; monocyte; nanoparticle; next generation; personalized medicine; prevent; programs; therapy outcome; translational oncology; treatment response

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.

首席研究员/项目总监（最后、第一、中间）：Afonin、Kirill、A 项目概要 如果医疗保健提供者配备生物相容、可生物降解、坚固且价格实惠的设备会怎样？ 将治疗方式与作用机制相结合的治疗方案会怎样？ 多功能技术具有学习能力，可以通过教育识别患者特定的疾病， 通过改变基本细胞过程来干扰它们的进展会怎样？ 可以提供一种额外的方法来控制患者的免疫反应并进一步推进有利的 毒性最小的治疗结果将成为一种游戏？ 帮助从源头预防、检测、诊断和治疗疾病和残疾。 在 MIRA (R35) 资金的支持下，我们设想了一个数据驱动的平台，SMART NANP（特定的、模块化的、 可调节、可重复且有针对性的核酸纳米颗粒），由自组装核酸编码。 核酸控制着所有生命形式的遗传信息流动，在以下方面发挥了重要作用： 除了其多样化的生物学之外，还获得有关主要细胞过程和疾病起源的新知识。 这些生物聚合物可以被编程为具有特定理化性质的 NANP， 决定 NANP 生物活性的功能，具有细胞重编程的无限可能性 我们最近发现不同的结构参数和 NANP 的组合物递送至初级人类免疫细胞，可以激活单核细胞和树突状细胞 生产 I 型和 III 型干扰素的这项关于 NANP 免疫识别的开创性工作强调了 该技术在疫苗和免疫治疗领域的不可预见的临床应用。 任何给定的 NANP 的结构-功能关系将允许有条件地启动其 通过一组嵌入的架构代码进行免疫识别或任何其他治疗活动。 概念，我们引入了治疗性 NANP 的两个正交概念，它们可以在 通过将这些突破和其他技术结合起来，人类癌细胞可以释放预先编程的疗法。 正如当前申请中所强调的，我的实验室的初步发现，并将它们整合到一个统一的 SMART NANP 网络，具有生物分布、免疫活性和治疗的可编程控制 模块，我们将推进当前针对传染病和癌症的疗法（通过 基于 NANP 的疫苗和免疫疗法）、心血管疾病（通过调节凝血） 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转化该技术， 拟议的计划将采用跨 SC 酸纳米技术核心领域的多学科方法， 免疫学、药物输送、转化肿瘤学和机器学习是该项目的长期目标。 将 SMART NANP 提升至临床使用水平。