肿瘤细胞对凋亡的不敏感性是抗化疗的主要机制。Smac/DIABLO模拟物被证明能有效克服因抗凋亡蛋白XIAP、cIAP1和cIAP2过度表达而导致的癌症获得性抗凋亡。本文描述了一种能够选择性激活癌细胞凋亡的双靶向肽。这个复合物由携带绑定αvβ3整合素配体的Smac/DIABLO短序列的荧光介孔有机硅纳米颗粒组成。双靶向肽@PMO在αvβ3阳性的HeLa细胞中对比αvβ3阴性的Ht29细胞表现出显著较高的毒性。在一系列αvβ3阳性的癌细胞中，@PMO与奥沙利铂的联合应用展示了协同效应，而XIAP过表达或整合素β3沉默能够克服其毒性。@PMO成功被αvβ3阳性细胞吸收，使其在许多癌症类型中能够重新敏感于凋亡。版权所有©2023 Di Giorgio、Ferino、Huang、Simonetti、Xodo和De Marco。

The refractoriness of tumor cells to apoptosis represents the main mechanism of resistance to chemotherapy. Smac/DIABLO mimetics proved to be effective in overcoming cancer-acquired resistance to apoptosis as a consequence of overexpression of the anti-apoptotic proteins XIAP, cIAP1, and cIAP2. In this work, we describe a dual-targeting peptide capable of selectively activating apoptosis in cancer cells. The complex consists of a fluorescent periodic mesoporous organosilica nanoparticle that carries the short sequences of Smac/DIABLO bound to the αvβ3-integrin ligand. The dual-targeting peptide @PMO shows significantly higher toxicity in αvβ3-positive HeLa cells with respect to αvβ3-negative Ht29 cells. @PMO exhibited synergistic effects in combination with oxaliplatin in a panel of αvβ3-positive cancer cells, while its toxicity is overcome by XIAP overexpression or integrin β3 silencing. The successful uptake of the molecule by αvβ3-positive cells makes @PMO promising for the re-sensitization to apoptosis of many cancer types.Copyright © 2023 Di Giorgio, Ferino, Huang, Simonetti, Xodo and De Marco.