Small molecule immuno-modulators such as agonists of Toll-like receptors (TLRs) are attractive compounds to stimulate innate immune cells toward potent antiviral and antitumor responses. However, small molecules rapidly enter the systemic circulation and cause "wasted inflammation". Hence, synthetic strategies to confine their radius of action to lymphoid tissue are of great relevance, to both enhance their efficacy and concomitantly limit toxicity. Here, we demonstrate that covalent conjugation of a small molecule TLR7/8 agonist immunomodulatory to a micelle-forming amphiphilic block copolymer greatly alters the pharmacokinetic profile, resulting in highly efficient lymphatic delivery. Moreover, we designed amphiphilic block copolymers in such a way to form thermodynamically stable micelles through π-π stacking between aromatic moieties, and we engineered the block copolymers to undergo an irreversible amphiphilic to hydrophilic transition in response to the acidic endosomal pH.

中文翻译：

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通过工程化的嵌段共聚物两亲物 - TLR7/8 激动剂偶联物实现淋巴结靶向免疫激活

小分子免疫调节剂，如 Toll 样受体 (TLR) 激动剂，是刺激先天免疫细胞产生有效抗病毒和抗肿瘤反应的有吸引力的化合物。然而，小分子会迅速进入体循环并导致“浪费性炎症”。因此，将其作用半径限制在淋巴组织的合成策略具有重要意义，以提高其功效并同时限制毒性。在这里，我们证明了小分子 TLR7/8 激动剂免疫调节与形成胶束的两亲嵌段共聚物的共价结合极大地改变了药代动力学特征，从而实现了高效的淋巴输送。此外，我们设计了两亲性嵌段共聚物，通过芳香部分之间的 π-π 堆积形成热力学稳定的胶束，