Nanoparticle-Based Strategies to Enhance PSMA-Targeted Radioligand Therapy: A Review of the Delivery, Co-Formulation, and Combination Landscape Surrounding Lutetium Lu 177 Vipivotide Tetraxetan (Pluvicto)

Abstract

Lutetium Lu 177 vipivotide tetraxetan (177Lu-PSMA-617; Pluvicto, Novartis) is a small-molecule, prostate-specific membrane antigen (PSMA)-targeted radioligand that has redefined the treatment of metastatic castration-resistant prostate cancer (mCRPC) and, following the 2026 approval based on the PSMAddition trial, hormone-sensitive disease as well. Despite its clinical success, the agent's pharmacokinetics as a small, rapidly cleared molecule impose real limits: short tumor residence time, off-target accumulation in the salivary glands, kidneys, and bone marrow, and heterogeneous efficacy in patients with low or discordant PSMA expression. Nanoparticle (NP) engineering has emerged as a complementary strategy to address these constraints by prolonging circulation time, increasing tumor-selective payload delivery through active PSMA targeting and passive enhanced permeability and retention (EPR) effects, enabling multimodal theranostic function, and offering routes to radioprotect healthy tissue. This review synthesizes preclinical and clinical literature (2019-2026) on nanoparticle platforms intersecting with PSMA-targeted radioligand therapy, including gold nanoparticles, polyamidoamine (PAMAM) dendrimers, liposomes and lipid nanoparticles, polymeric micelles, and iron oxide nanoparticles. We describe how these platforms have been used for radionuclide labeling, combinatorial drug delivery, and multimodal imaging, and we summarize the clinical trial evidence for 177Lu-PSMA-617 itself (VISION, TheraP, PSMAfore, PSMAddition) to contextualize the toxicity and efficacy gaps that nanomedicine approaches are designed to close. We conclude by outlining translational barriers -- reproducible manufacturing, comparative organ-level dosimetry, and regulatory pathways for radiolabeled nanomedicines -- that must be resolved before nanoparticle-Pluvicto hybrids can reach the clinic.