Engineered prostate-specific membrane antigen-targeted liposomal nanoplatform integrating near-infrared fluorescence, ultrasound, and magnetic resonance imaging for precision prostate cancer imaging

• PSMA-targeted liposomes co-loaded with ICG, PFP, and MnO 2 enable tri-modal imaging. • Tailored liposomal architecture synchronizes NIR fluorescence, US, and MRI signals. • Engineered surface boosts PSMA-specific tumor targeting and cellular internalization. • Tri-modal imaging demonstrates 4.6 × NIR and 3.2 × US enhancement in PSMA + tumors. • Liposomal nanoplatform exhibits strong translational potential for image-guided diagnosis. Accurate and early diagnosis of prostate cancer remains clinically challenging due to the limitations of single-modality imaging. A prostate-specific membrane antigen (PSMA)-functionalized tri-modal liposomal nanoplatform was developed by co-loading indocyanine green (ICG), perfluoropentane (PFP), and manganese dioxide (MnO 2 ) to enable near-infrared fluorescence (NIR), ultrasonography (US), and magnetic resonance imaging (MRI). Anti-PSMA antibodies were electrostatically adsorbed onto the liposomal surface to provide PSMA-directed targeting potential. In vitro, PFP/ICG/Lip/MnO 2 @PSMA + showed enhanced NIR fluorescence compared with free ICG at matched concentrations, achieved > 3.5-fold higher US contrast with increasing PFP volume fraction, and showed a linear correlation between R 1 (1/T 1 ) and Mn concentration. PSMA-positive LNCaP cells showed 3.6-fold higher uptake than non-targeted liposomes. In vivo studies revealed biphasic blood clearance based on Mn quantification (elimination half-life, 4.29 h) and progressive tumor enrichment, with the highest tumor Mn uptake (∼8.7% ID/g) observed at 8 h post-injection. Consistently, they generated stronger NIR fluorescence, US contrast, and T 1 -weighted MRI signals in LNCaP xenografts. Histology and serum biochemistry revealed no detectable systemic toxicity.