Mechanical stiffness-promoted tumor tagging to navigate radiopharmaceuticals: Single-cell RNA sequencing revealed the fate of MSC after tumor homing

Radiopharmaceutical imaging and targeted radionuclide therapy rely on endogenous molecular targets which are frequently heterogeneous, absent, or lost during cancer progression. We developed SMART, a Stiffness-responsive Mesenchymal stem cell (MSC)-Assisted Relayed tumor-Targeting platform that converts elevated matrix stiffness, a conserved biophysical feature of tumors, into localized expression of synthetic radiopharmaceutical targets. Engineered MSCs sensing stiff tumor microenvironments induced tumor-restricted expression of prostate-specific membrane antigen (PSMA), enabling 68Ga-PSMA-617 positron emission tomography (PET) imaging and 177Lu-AB-PSMA-617 therapy across diverse tumor models. SMART-enabled PET improved detection sensitivity relative to 18F-fluorodeoxyglucose PET, including in brain, lung, and bone metastases. The platform is modular, extendable to targets such as somatostatin receptor 2, and compatible with induced pluripotent stem cell (iPSC)-derived MSCs. SMART therefore decouples radiotheranostic performance from endogenous biomarker status and establishes a generalizable strategy for targeting biophysical hallmarks of cancer.