PSMA-directed nanoprobe enabling precision imaging and MR-guided chemoradiotherapy in prostate cancer

Imaging-guided radiotherapy can improve the precision and therapeutic efficacy of prostate cancer (PCa). However, advanced PCa often exhibits diffuse intraprostatic infiltration, extracapsular extension, and intrinsic radioresistance, complicating accurate tumor identification and adaptive radiation delivery without increasing damage to surrounding healthy tissues. Herein, we report the design of prostate-specific membrane antigen (PSMA) targeted platinum(IV) prodrug nanoprobes (GPNPs) with high MR imaging sensitivity and PSMA specificity for enhanced MR-guided chemoradiotherapy of locally advanced PCa. The GPNPs are constructed through the co-assembly of a Pt(IV)-PSMA-1 targeting prodrug and a Pt(IV)-Gd(III) imaging prodrug, yielding stable nanoprobes with r₁ relaxivity as high as 18.59 mM^-1 s^-1. Through selective targeting of PSMA-positive tumor cells, GPNPs achieved enhanced cellular uptake and tumor accumulation, enabling more accurate MR imaging and tumor lesion identification. The GPNPs underwent activation at reductive tumor microenvironment and upon X-ray irradiation, they can overcome radioresistance by improved reactive oxygen species generation and DNA damage amplification. The GPNPs induced robust tumor growth inhibition in vivo with minimal systemic toxicity, while concurrently suppressing lung metastasis through enhanced CD8⁺ T-cell infiltration and increased effector cytokine production. These results highlight GPNPs as a potent and versatile nanoplatform for precision imaging of locally advanced PCa and enhanced MR-guided chemoradiotherapy.