诱导和监测细胞凋亡是评估药物治疗效果和避免过度治疗的关键。尽管通过评估细胞膜完整性来监测细胞凋亡取得了有希望的进展，但细胞健康状态因平衡蛋白质稳态紊乱而引起的慢性损害是不可见的，很难被检测到。作为细胞凋亡指标，聚集蛋白质的成像提供了一个新的方向。在这里，我们设计了一个用于成像聚集蛋白质进行自报告的肽结合探针（QRKN），能够通过诱导线粒体功能失调来自报告细胞凋亡。具体而言，QRKN能够通过过表达的B型溶酶体蛋白酶（CB）在肿瘤细胞中被切割成α-螺旋形成部分（QRK）和含偶氮基修饰的小分子部分（N）。QRK部分能破坏线粒体膜，促进细胞色素c（Cyt c）外流和半胱天冬酶3（caspase 3）的表达。另外，N部分能抑制线粒体复合物IV（Mito-IV）的活性，降低三磷酸腺苷（ATP）的表达水平。两条信号通路共同诱导线粒体功能失调，最终导致蛋白质聚集和细胞凋亡。与此同时，细胞凋亡过程可以基于QRKN进行监测，该探针对聚集蛋白质引发的粘度变化非常敏感。该自报告探针可以监测治疗反应并提供有价值的诊断信息。

Inducing and monitoring cell apoptosis in a real-time manner are crucial for evaluating the therapeutic effect of drugs and avoiding excessive treatment. Although promising advancements have been made to monitor cell apoptosis by assessing cell membrane integrity, the chronic compromise of cellular fitness caused by imbalance proteostasis is not visible and hard to be detected. As an indicator for cell apoptosis, imaging of aggregated proteins provides a new direction. Herein, we design a peptide-conjugated probe (QRKN) that can induce mitochondrial dysfunction for self-reporting cell apoptosis by imaging aggregated proteins. Specifically, QRKN can be cleaved into the α-helix-forming part (QRK) and azide-modified small-molecule part (N) by overexpressed cathepsin B (CB) in tumor cells. The QRK part can destroy the mitochondrial membrane and promote cytochrome c (Cyt c) efflux and caspase 3 expression. The other N part can inhibit the activity of mitochondrial complex IV (Mito-IV) and decrease the expression level of adenosine triphosphate (ATP). Two signaling pathways cooperatively induce mitochondrial dysfunction, resulting in protein aggregation and cell apoptosis ultimately. Meanwhile, the cell apoptosis process can be monitored based on QRKN, which is highly sensitive to the aggregated protein-triggered viscosity change. The self-reporting probe can monitor therapeutic responses and provide valuable diagnosis information.