Small molecule theranostic agents suffer from fast blood clearance whereas nanoparticle ones are incapable of molecular functions and often nondegradable. We propose to bridge the gap between nanoparticles and small molecule agents based on self-immolative polymers which undergo triggered cascade depolymerization at the chain level. Amphiphilic block copolymers containing side chain-functionalized depolymerizable block self-assemble into micellar nanoparticles. Upon triggering with reactive oxygen species (ROS) and acidic pH, nanoparticles self-immolate into electron-deficient small molecule azaquinone methide (AQM) derivatives, which are capable of efficient addition reactions with biologically relevant nucleophiles. By taking advantage of this feature, we achieve stimuli-activatable ¹⁹F NMR/MR imaging and ¹⁹F/¹H dual-modality MR imaging. Upon cellular uptake, AQMs generated during depolymerization react with intracellular thiol-relevant substrates including GSH and thiol-containing proteins. Starting from self-immolative nanoparticles functionalized with DOTA-Gd, we demonstrate unprecedented long-term in vivo ¹H MR imaging of tumor-bearing mice via the in situ covalent trapping strategy.

小分子治疗药物的血液清除速度很快，而纳米颗粒的分子治疗药物则无法发挥分子功能，并且通常不可降解。我们建议弥合纳米粒子和基于自消灭聚合物的小分子试剂之间的差距，这些聚合物在链水平发生触发的级联解聚。含有侧链官能化的可解聚嵌段的两亲嵌段共聚物可自组装成胶束纳米颗粒。在被活性氧（ROS）和酸性pH触发后，纳米粒子会自焚成电子缺陷型小分子氮杂醌甲基化物（AQM）衍生物，能够与生物学相关的亲核试剂进行有效的加成反应。通过利用此功能，我们实现了刺激激活的¹⁹ F NMR / MR成像和¹⁹ F / ¹ H双模态MR成像。细胞吸收后，解聚过程中产生的AQM与细胞内与巯基相关的底物（包括GSH和含巯基的蛋白质）反应。从用DOTA-Gd功能化的自焚纳米颗粒开始，我们证明了通过原位共价捕获策略对荷瘤小鼠进行前所未有的长期体内 ¹ H MR成像。