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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE337702 | GEO | 2026/07/14

REPOSITORIES: GEO

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