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 ZnGa 2 O 4 :Cr 3+ 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.
Epstein–Barr nuclear antigen 1 (EBNA1), a sequence-specific DNA binding protein of Epstein–Barr virus (EBV), is essential for viral genome replication and maintenance and is therefore an attractive target for the therapeutic intervention of EBV-associated cancers. Several EBNA1-specific inhibitors have demonstrated the ability to block EBNA1 function in vitro, but practical delivery strategies for these inhibitors in vivo are still lacking. Here, we report an intelligent hierarchical targeting theranostic nanosystem (denoted as mZGOCS@MnO2–P5) that integrates an azide (N3) terminal dual-targeting peptide (N3–P5), a tumor microenvironment-responsive degradable MnO2 nanosheet, and a mesoporous ZnGa2O4:Cr3+, Sn4+ near-infrared persistent luminescence (NIR-PL) nanosphere (mZGOCS). In our design, mZGOCS@MnO2–P5 enables primarily targeting of the EBV-specific oncoprotein LMP1 (an EBV-encoded transmembrane protein) via the LMP1 targeting motif within P5. Once internalized into cells, the MnO2 nanosheet would be degraded in the acidic and reducing tumor microenvironment, simultaneously releasing P5 and recovering the NIR-PL of ZnGa2O4:Cr3+, Sn4+ initially quenched by the MnO2 nanosheet, thereby providing an autofluorescence interference-free NIR-PL imaging signal for monitoring the delivery efficacy of P5. The released P5 can secondarily target EBNA1 via the EBNA1 binding motif, blocking its function and thus inhibiting the growth of EBV-positive tumors. The feasibility of our developed hierarchical targeting theranostic nanosystem is well demonstrated both in vitro and in vivo, highlighting the huge translational potential of mZGOCS@MnO2–P5 in EBV-associated cancer therapy.
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