DLL4/VEGF bispecific molecularly imprinted nanomissile for robust tumor therapy.

Tumor-induced angiogenesis plays a pivotal role in the progression and expansion of solid tumors, making anti-angiogenic therapies a promising strategy in cancer treatment. However, compensatory angiogenesis, which can drive drug resistance and tumor recurrence, poses significant challenges in anti-angiogenic therapy. Therefore, improved anti-tumor angiogenesis therapy has become a critical necessity. Herein, we present a bispecific molecularly imprinted nanomissile (bsMINM) engineered to simultaneously target and inhibit both vascular endothelial growth factor (VEGF) and Delta-like 4 (DLL4). By blocking these two pivotal signals in tumor angiogenesis, bsMINM offers a potent "one-stone-for-two-birds" strategy that markedly enhances anti-tumor angiogenesis. The bsMINM features tailor-made binding sites for the N-epitopes of both VEGF and DLL4. This design allows bsMINM to persist at tumor sites effectively and diminish the negative feedback loop between VEGF and DLL4. The bsMINM inhibits VEGF-VEGFR signaling pathway in vascular endothelial cells and DLL4-Notch signaling pathway in both vascular endothelial cells and tumor cells, resulting in significant anti-tumor angiogenesis and growth inhibition. In the MCF-7 xenograft model, bsMINM exhibited a notable efficacy in restraining tumor progression while concurrently diminishing the self-renewal potential of cancer cells. This study pioneers the construction of the first bsMINM with inherent, enhanced anti-angiogenic effects achieved through dual blockades. The platform's bispecific recognition capability opens a new avenue for tumor treatment and shows significant promise in addressing issues caused by signaling pathway compensation.