Lysosomes have become an important target for anticancer therapeutics because lysosomal cell death bypasses the classical caspase-dependent apoptosis pathway, enabling the targeting of apoptosis- and drug-resistant cancers. However, only a few small molecules-mostly repurposed drugs-have been tested so far, and these typically exhibit low cancer selectivity, making them suitable only for combination therapies. Here, we show that mixed-charge nanoparticles covered with certain ratios of positively and negatively charged ligands can selectively target lysosomes in cancerous cells while exhibiting only marginal cytotoxicity towards normal cells. This selectivity results from distinct pH-dependent aggregation events, starting from the formation of small, endocytosis-prone clusters at cell surfaces and ending with the formation of large and well-ordered nanoparticle assemblies and crystals inside cancer lysosomes. These assemblies cannot be cleared by exocytosis and cause lysosome swelling, which gradually disrupts the integrity of lysosomal membranes, ultimately impairing lysosomal functions and triggering cell death.

中文翻译：

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溶酶体中混合电荷纳米粒子的靶向结晶诱导癌细胞的选择性死亡。

溶酶体已成为抗癌治疗的重要靶标，因为溶酶体细胞死亡绕过了经典的caspase依赖性凋亡途径，从而能够靶向凋亡和耐药性癌症。但是，到目前为止，仅测试了少数几个小分子药物（主要是重新用途的药物），这些药物通常表现出较低的癌症选择性，使其仅适用于联合疗法。在这里，我们表明，覆盖有一定比例的带正电和带负电的配体的混合电荷纳米粒子可以选择性地靶向癌细胞中的溶酶体，而对正常细胞仅表现出很小的细胞毒性。这种选择性是由不同的pH依赖性聚集事件引起的，从形成小的，易于在细胞表面发生内吞作用的簇，并以在癌症溶酶体内形成大而有序的纳米粒子集合和晶体为结尾。这些组装物不能通过胞吐作用清除并引起溶酶体溶胀，从而逐渐破坏溶酶体膜的完整性，最终损害溶酶体功能并触发细胞死亡。