Nanotechnology in Prostate Cancer: PSMA-Targeted Nanoplatforms, TME-Responsive Therapy, Immunomodulation, and Clinical Translation Challenges.

The field of nanotechnology has demonstrated considerable potential in the diagnosis and treatment of prostate cancer, particularly through the use of prostate-specific membrane antigen (PSMA)-targeted platforms and tumor microenvironment (TME)-responsive systems. In the context of diagnosis, nanoparticle-based molecular imaging probes have been shown to enhance detection sensitivity and specificity. These probes include superparamagnetic iron oxide, which is utilized in magnetic resonance imaging, and near-infrared fluorescent nanomicelles. Additionally, nanostructured liquid biopsy systems have demonstrated the capability to capture circulating tumor cells, exosomes, and circulating tumor DNA with high sensitivity, facilitating non-invasive genotyping and treatment monitoring. In the field of therapeutics, PSMA-targeted liposomes, polymeric nanoparticles, and inorganic nanocarriers have demonstrated efficacy in enhancing the delivery of chemotherapeutics, gene-editing tools (eg, CRISPR/Cas9, siRNA), and immunomodulators. These delivery mechanisms are equipped with TME-responsive release mechanisms (eg, pH, enzyme, redox) that enable the spatiotemporal control of drug release. Nanotechnology offers multi-level strategies to overcome multidrug resistance in castration-resistant prostate cancer, including PROTAC-mediated protein degradation, ferroptosis induction, and synergistic chemo-immunotherapy. Multifunctional theranostic nanoplatforms integrating imaging and therapy enable real-time efficacy assessment and personalized treatment adaptation. Emerging green synthesis approaches that utilize agricultural byproducts and bio-inspired platforms (eg, cell membrane-coated nanoparticles) present sustainable and biocompatible alternatives. Concurrently, artificial intelligence (AI) holds the potential to expedite the design of nanocarriers. Despite the advancement of several nanomedicines to clinical trials, significant translational barriers persist. These include heterogeneous PSMA expression (15-37% of castration-resistant prostate cancer cases are PSMA-negative), suboptimal enhanced permeability and retention effect in humans, long-term safety concerns, manufacturing hurdles, and regulatory gaps. This narrative review methodically examines the applications of nanotechnology in prostate cancer. It critically analyzes the clinical translation challenges encountered during clinical trials and discusses future directions, including smart responsive systems, multimodal immunotherapy, and AI-assisted nanomedicine design.