EBNA1 Targeted Ultra‐Small Near‐Infrared Persistent Luminescent Nano‐Inhibitor for Theranostics of EBV‐Associated Cancer

This work reports a novel EBNA1 nano-inhibitor based on EBNA1-specific peptide inhibitor (P4) functionalized ZnGa₂O₄:Cr³⁺ ultra-small near-infrared persistent luminescent (NIR-PL) nanoparticles (ZGOC-P4) to overcome the utilization limitations of current EBNA1 inhibitors in vivo. ZGOC-P4 enables fast nuclear internalization, selective toxicity against EBV-positive cells, autofluorescence interference-free NIR-PL tracing, and outstanding EBV-positive tumor inhibition efficacy, revealing the practicability of the nano-inhibitor.

Abstract

Epstein–Barr virus (EBV) is a well-recognized oncogenic virus that promotes several lymphoid and epithelial cancers. The Epstein–Barr nuclear antigen 1 (EBNA1), which is known to be expressed in all EBV-positive cancers, plays a vital role in viral genome replication and maintenance and is therefore emerged as an attractive target for clinical intervention. Several EBNA1 inhibitors have shown potency in the growth inhibition of EBV-positive cancers, yet low bioavailability and in vivo unmonitored nature hamper their further implementation. Here a novel EBNA1 nano-inhibitor based on EBNA1-specific peptide inhibitor (P4) functionalized ZnGa₂O₄:Cr³⁺ ultra-small near-infrared persistent luminescent (NIR-PL) nanoparticles (ZGOC-P4) is developed. Owing to the specific binding to EBNA1, ZGOC-P4 nano-inhibitor can quickly achieve nuclear internalization in EBV-positive nasopharyngeal carcinoma (NPC) cells (C666-1) and selectively inhibit their growth. In sharp contrast, ZGOC-P4 nano-inhibitor shows no inhibition effect on EBV-negative NPC cells (HK-1). Moreover, the results indicate that the well-designed nano-inhibitor enables efficient tumor-targeting accumulation in NPC xenograft model under the monitoring of autofluorescence interference-free NIR-PL imaging in vivo and suppresses EBV-associated tumor growth with an inhibition rate of 61.6%. This work highlights the potency of ZGOC-P4 on NPC treatment and may provide new sight into future research on EBV-associated diseases.