Xiujie Yang, Qi Yin, Kui Li, Jianze Wang, Rui Song, Haoyi Zhou, Shu Han, Linyu Zhang, Yuwen Zeng, Da Xu, Feng Wang, Shixin Zhou, Yang Yang, Hua Zhu, Chunhong Zheng, Yang Li, Zhi Yang, Xing Yang, Zhaofei Liu
Radiopharmaceutical-based imaging and targeted radionuclide therapy are often limited by heterogeneous or absent molecular targets in tumors. Here, we present a stiffness-responsive mesenchymal stem cell (MSC)-assisted relayed tumor-targeting (SMART) platform that converts matrix stiffness into a programmable molecular entry point for radiotheranostics. Engineered MSCs sense elevated mechanical stiffness within the tumor microenvironment and induce localized expression of synthetic biomarkers, thereby enabling radiopharmaceutical targeting independent of endogenous target availability. As a proof of concept, SMART-driven expression of prostate-specific membrane antigen (PSMA) enables sensitive tumor detection by 68Ga-PSMA-617 positron emission tomography (PET) and effective treatment with 177Lu-AB-PSMA-617 across multiple tumor models, with improved sensitivity and reduced off-target uptake compared with conventional 18F-fluorodeoxyglucose PET. This platform is readily adaptable to alternative synthetic targets and induced pluripotent stem cell (iPSC)-derived MSCs. By translating a universal physical feature of tumors into an actionable molecular signature, SMART expands the scope of precision radiotheranostics beyond native biomarkers.