Doxorubicin (Dox) is an effective anticancer molecule, but its clinical efficacy is limited by strong cardiotoxic side effects. Lysosomal dysfunction has recently been proposed as a new mechanism of Dox-induced cardiomyopathy. However, to date, there is a paucity of therapeutic approaches capable of restoring lysosomal acidification and function in the heart. Methods: We designed novel poly(lactic-co-glycolic acid) (PLGA)-grafted silica nanoparticles (NPs) and investigated their therapeutic potential in the primary prevention of Dox cardiotoxicity in cardiomyocytes and mice. Results: We showed that NPs-PLGA internalized rapidly in cardiomyocytes and accumulated inside the lysosomes. Mechanistically, NPs-PLGA restored lysosomal acidification in the presence of doxorubicin or bafilomycin A1, thereby improving lysosomal function and autophagic flux. Importantly, NPs-PLGA mitigated Dox-related mitochondrial dysfunction and oxidative stress, two main mechanisms of cardiotoxicity. In vivo, inhalation of NPs-PLGA led to effective and rapid targeting of the myocardium, which prevented Dox-induced adverse remodeling and cardiac dysfunction in mice. Conclusion: Our findings demonstrate a pivotal role for lysosomal dysfunction in Dox-induced cardiomyopathy and highlight for the first time that pulmonary-driven NPs-PLGA administration is a promising strategy against anthracycline cardiotoxicity.

中文翻译：

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吸入酸性纳米颗粒可通过改善溶酶体功能来预防阿霉素心脏毒性。

阿霉素（Dox）是一种有效的抗癌分子，但其临床疗效因强烈的心脏毒性副作用而受到限制。溶酶体功能障碍最近被提出作为阿霉素诱导的心肌病的新机制。然而，迄今为止，能够恢复溶酶体酸化和心脏功能的治疗方法很少。方法：我们设计了新型聚乳酸乙醇酸 (PLGA) 接枝二氧化硅纳米粒子 (NP)，并研究了其在心肌细胞和小鼠中一级预防 Dox 心脏毒性的治疗潜力。结果：我们发现 NPs-PLGA 在心肌细胞中快速内化并在溶酶体内积累。从机制上讲，NPs-PLGA 在阿霉素或巴弗洛霉素 A1 存在的情况下恢复溶酶体酸化，从而改善溶酶体功能和自噬通量。重要的是，NPs-PLGA 减轻了 Dox 相关的线粒体功能障碍和氧化应激，这是心脏毒性的两个主要机制。在体内，吸入 NPs-PLGA 可以有效、快速地靶向心肌，从而防止 Dox 诱导的小鼠不良重塑和心脏功能障碍。结论：我们的研究结果证明了溶酶体功能障碍在 Dox 诱导的心肌病中发挥着关键作用，并首次强调肺部驱动的 NPs-PLGA 给药是对抗蒽环类药物心脏毒性的一种有前景的策略。