In Situ Self‐Assembled Molecular Fortifying Agent for Enhanced Retention and Therapeutic Efficacy of Radiopharmaceuticals

ABSTRACT

Targeted radionuclide therapy is often limited by the rapid clearance of radiopharmaceuticals from tumor tissues, which reduces the delivered radiation dose and compromises therapeutic efficacy. To address this challenge, we developed a molecular‐fortifying agent (MFA) strategy based on in situ self‐assembly to extend the tumor retention of radioligands. This approach involves the intravenous administration of a DBCO‐modified radioligand ( ^{1 7 7} Lu‐FAPI‐DBCO) for tumor‐specific targeting, followed by injection of the MFA. Upon reaching the tumor microenvironment, the hydrophilic segment of MFA is cleaved by overexpressed fibroblast activation protein‐α. The resulting exposure of the KLVFF motif alters the hydrophilic‐hydrophobic balance, driving its rapid self‐assembly via hydrophobic interaction and hydrogen bonding into dense nanofiber networks with abundant azide anchoring sites concentrated on the fiber surface. These nanofibers subsequently capture the pre‐accumulated radioligands via a bio‐orthogonal click reaction, covalently immobilizing them in situ. This assembly‐induced retention effect significantly prolongs the intratumoral residence time of the radiopharmaceutical without increasing its accumulation in non‐target organs. In a tumor model, the MFA strategy enhanced tumor retention, achieved an 88.7% tumor growth inhibition rate, and demonstrated favorable biosafety. Collectively, this strategy offers a promising and generalizable platform for improving the therapeutic profile of radiopharmaceuticals.