铂类化疗已广泛应用于临床癌症治疗，但耐药性是导致癌症患者预后不良的主要障碍。长链非编码RNA（lncRNA）因其在调节耐药性等癌症进展中的重要作用而被认为是一种新的癌症治疗靶点。然而，有效干预lncRNA的表达仍然面临挑战，因为它们通常位于各种亚细胞器（例如细胞核、线粒体和内质网）。我们在此开发了一种内体 pH 响应纳米颗粒 (NP) 平台，用于小干扰 RNA (siRNA) 和顺铂前药共同递送和有效的顺铂耐药性肝细胞癌 (HCC) 治疗。该共递送纳米平台由亲水性聚乙二醇（PEG）外壳和疏水性聚（2-（二异丙氨基）乙基甲基丙烯酸酯）（PDPA）核心组成，其中顺铂前药和核靶向两亲肽（NTPA）的静电复合物和siRNA被封装。静脉注射并被肿瘤细胞摄取后，内体pH可以触发纳米平台的解离，并通过“质子海绵”效应增强负载的顺铂前药和NTPA/siRNA复合物的内体逃逸。随后，NTPA/siRNA复合物可以特异性地将siRNA转运到细胞核中，并通过沉默主要位于细胞核的lncRNA转移相关肺腺癌转录物1（lncMALAT1）的表达来有效逆转顺铂耐药性，最终抑制顺铂耐药性HCC的生长肿瘤。版权所有 © 2024 王、李、徐、赵、孙、徐和李。

Platinum-based chemotherapy has been widely used for clinical cancer treatment, but drug resistance is the main barrier to induce the poor prognosis of cancer patients. Long non-coding RNAs (lncRNAs) have been recognized as a type of new cancer therapeutic targets due to their important role in regulating cancer progression such as drug resistance. However, it is still challenged to effectively intervene the expression of lncRNAs as they are usually located at various subcellular organelles (e.g., nucleus, mitochondrion, and endoplasmic reticulum). We herein developed an endosomal pH-responsive nanoparticle (NP) platform for small interfering RNA (siRNA) and cisplatin prodrug co-delivery and effective cisplatin-resistant hepatocellular carcinoma (HCC) therapy. This co-delivery nanoplatform is comprised of a hydrophilic polyethylene glycol (PEG) shell and a hydrophobic poly (2-(diisopropylamino)ethyl methacrylate) (PDPA) core, in which cisplatin prodrug and electrostatic complexes of nucleus-targeting amphiphilic peptide (NTPA) and siRNA are encapsulated. After intravenous injection and then uptake by tumor cells, the endosomal pH could trigger the dissociation of nanoplatform and enhance the endosomal escape of loaded cisplatin prodrug and NTPA/siRNA complexes via the "proton sponge" effect. Subsequently, the NTPA/siRNA complexes could specifically transport siRNA into the nucleus and efficiently reverse cisplatin resistance via silencing the expression of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (lncMALAT1) mainly localized in the nucleus, ultimately inhibiting the growth of cisplatin-resistant HCC tumor.Copyright © 2024 Wang, Li, Xu, Zhao, Sun, Xu and Li.