Rethinking the PSMA-mediated tumor targeting of nanocarrier and potentiating co-delivery of PARP/EZH2 inhibitors for robust prostate cancer treatment.

Ligand-mediated targeting of prostate-specific membrane antigen (PSMA) is a prominent strategy in prostate cancer (PCa) theranostics. However, the conventional mechanism of PSMA-targeted nanomedicines, based on passive enhanced permeability and retention (EPR) from leaky vasculature followed by active receptor-mediated uptake, has been challenged by emerging evidence of direct endothelial transport. Here, we developed a PSMA-targeted silicasome (tSil) via peptide modification, which achieved markedly enhanced tumor accumulation compared with non-targeting control in subcutaneous, orthotopic, and bone metastatic PCa models. The ultrastructural transmission electron microscopy and in vivo competitive blocking assays revealed that, in non-leaky vasculature settings where the EPR effect is limited, tSil utilized both non-receptor and PSMA-dependent active transcytosis to traverse endothelial cells and penetrate tumor parenchyma with improved cellular uptake efficiency. To explore the therapeutic potential of this active targeting in metastatic castration-resistant prostate cancer (mCRPC), we co-encapsulated the PARP inhibitor rucaparib and EZH2 inhibitor tazemetostat in tSil to synergistically induce DNA damage and apoptosis. In both subcutaneous and orthotopic models, the tSil platform exhibited superior antitumor efficacy relative to non-targeting formulation. Co-delivery of the PARP/EZH2 inhibitors also upregulated PD-L1 expression and enhanced cytotoxic T cell infiltration, prompting combination with immune checkpoint blockade, which yielded improved outcomes in orthotopic and challenging bone metastasis mouse models. Collectively, this work presents a promising therapeutic strategy for PCa and offers insights into the design of ligand-mediated nanomedicines for efficient tumor drug delivery.