Reactive oxygen species (ROS)-activated prodrugs can potentially improve the selectivity of chemotherapeutics. However, the inability to release sufficient drugs at tumor sites due to the paucity of ROS, which is required for prodrug activation usually limits the antitumor potency. Herein, a delivery nanosystem with self-amplifiable drug release pattern is constructed by encapsulating a tumor specificity ROS inducer NAD(P)H: quinone oxidoreductase-1 (NQO1)-responsive hemicyanine fluorescent dye (NCyNH₂) in a ROS-responsive self-immolative polyprodrug nanoparticle for orchestrated oxidation-chemotherapy. In response to ROS stimulation, the self-immolative polyprodrug can degrade and release doxorubicin (DOX) through a domino-like fragmentation, which can impart advanced attributes of this nanosystem such as minimum cleavage events required and maximum cleavage speed for disintegration. Thus, the NCyNH₂-loaded self-immolative polyprodrug nanoparticle (SIPN) could be dissociated in response to endogenous ROS, triggering the release of DOX and NCyNH₂. Subsequently, the NCyNH₂ could be activated by intratumoral overexpressed NQO1 to generate additional ROS, which further induces the amplifiable degradation of self-immolative polyprodrug to release sufficient drugs. The in vitro and in vivo studies consistently demonstrate that SIPN amplifies the drug release efficiency of ROS-responsive polyprodrug by specifically upregulating intratumoral ROS levels, resulting in significant antitumor efficacy with minimal side effects.

活性氧 (ROS) 激活的前药可能会提高化疗药物的选择性。然而，由于前药激活所需的 ROS 缺乏，无法在肿瘤部位释放足够的药物通常会限制抗肿瘤效力。在此，通过将肿瘤特异性 ROS 诱导剂 NAD(P)H：醌氧化还原酶-1 (NQO1) 响应的半花青素荧光染料 (NCyNH ₂ ) 封装在 ROS 响应自自燃聚前体药物纳米颗粒用于精心策划的氧化化疗。为了响应 ROS 刺激，自焚多聚前体药物可以通过多米诺骨牌样碎裂降解和释放多柔比星 (DOX)，这可以赋予该纳米系统的高级属性，例如所需的最小裂解事件和崩解的最大裂解速度。因此，负载 NCyNH ₂的自焚聚前体药物纳米颗粒 (SIPN) 可以解离以响应内源性 ROS，触发 DOX 和 NCyNH ₂的释放。随后，NCyNH ₂可被瘤内过表达的 NQO1 激活，产生额外的 ROS，进一步诱导自焚聚前体药物的可放大降解，以释放足够的药物。体外和_体内研究一致表明，SIPN 通过特异性上调肿瘤内 ROS 水平来增强 ROS 响应性聚前体药物的药物释放效率，从而产生显着的抗肿瘤功效和最小的副作用。