To develop multifunctional small-molecule prodrugs is highly desirable for cancer treatment but remains challenging in intrinsic traceability. As an acid-cleavable linkage, a Schiff bases benefiting from its distinctive fluorescence quenching ability was selected to prepare a small-molecule prodrug with cancer-targeted and self-indicating. In this study, we designed and developed a multifunctional self-assembled nanobomb of amphiphilic TPE-Lenalidomide prodrug, which comprises a hydrophobic aggregation-induced emission (AIE) probe 4-(1,2,2-triphenylvinyl)benzaldehyde (TPE-CHO) and a hydrophilic anticancer drug Lenalidomide via a Schiff base linkage. We investigated the synergistic effect of d-PET and C═N isomerization which would keep the fluorescence of TPE-Lenalidomide in the “always off” state by density functional theory (DFT) calculation. Once reaching the pathological site, such a vesicular nanobomb of TPE-Lenalidomide will be acidolyzed to release the AIE probe and Lenalidomide molecules simultaneously, consequently realizing high-efficiency effects of tumor imaging and cancer therapy (cell viability: normal cell L929, ∼79.49%; cancer cell 4T1, ∼27.08%; p = 0.000118). This work may pave an avenue to prepare small-molecule prodrugs for tumor-targeted diagnosis and cancer therapy.@en