The redox status of cancer cells is well regulated by the balance between the reactive oxygen species (ROS) generation and elimination. Thus, the overall elevation of ROS level above the cellular tolerability threshold would lead to apoptotic or necrotic cell death. Herein, cinnamaldehyde (CA), a kind of oxidative stress amplified agent, was combined with photosensitizer pheophorbide A (PA) to promote the generation of ROS though synergistically endogenous and exogenous pathways. Firstly, acid-responsive polygalactose-co-polycinnamaldehyde polyprodrug (termed as PGCA) was synthesized, which could self-assemble into stable nanoparticles for the delivery of PA (termed as PGCA@PA NPs). The abundant expression of galactose receptor on tumor cells facilitated the positive targeting and cellular uptake efficiency of PGCA@PA NPs, after which PA could be synchronously released in company with the intracellular disassembly of PGCA NPs, due to the detaching of CA moieties under acidic microenvironment in endo/lysosomal compartment. Significantly increased ROS level was induced by the combined action of CA and PA with light irradiation, resulting in dramatically enhanced apoptosis of cancer cells. Importantly, intravenous injection of PGCA@PA NPs potently inhibited the tumor growth in hepatocellular carcinoma with negligible adverse effects. Moreover, combined with anti-programmed cell death protein 1 (anti-PD-1) therapy, PGCA@PA NPs treatment elicited anti-melanoma T-cell immune response and significantly promoted T cells infiltration in tumors. Hence, this novel polyprodrug nano delivery system was able to target and modulate the unique redox regulatory mechanisms of cancer cells through endogenous and exogenous pathways, providing a feasible approach to achieve synergetic therapeutic activity and selectivity.

癌细胞的氧化还原状态受到活性氧（ROS）生成和消除之间的平衡的良好调节。因此，ROS水平的总体升高高于细胞耐受性阈值将导致凋亡或坏死性细胞死亡。在这里，肉桂醛（CA），一种氧化应激放大剂，与光敏剂脱镁叶绿酸A（PA）结合，通过协同的内源性和外源性途径促进ROS的产生。首先，合成了酸响应性聚半乳糖-聚肉桂醛共聚多药（称为PGCA），它可以自组装成稳定的纳米颗粒用于PA的递送（称为PGCA @ PA NPs）。半乳糖受体在肿瘤细胞上的大量表达促进了PGCA @ PA NPs的正向靶向和细胞摄取效率，之后，由于内/溶酶体区室中酸性微环境下CA部分的分离，PA可以与PGCA NPs的细胞内分解同步释放。CA和PA与光照射的联合作用诱导了ROS水平的显着升高，导致癌细胞的凋亡显着增强。重要的是，静脉注射PGCA @ PA NPs可以有效地抑制肝细胞癌中的肿瘤生长，且副作用可忽略不计。此外，PGCA @ PA NPs与抗程序性细胞死亡蛋白1（anti-PD-1）治疗相结合，可引起抗黑素瘤T细胞免疫反应，并显着促进肿瘤中T细胞的浸润。因此，