癌症多药耐药（MDR）是严重影响化疗疗效的重要因素。在各种绕过MDR的方法中，使用细胞因子如肿瘤坏死因子α（TNFα）是一种有吸引力的方法，它通过免疫治疗反应和凋亡/促炎途径发挥抗肿瘤效应。然而，如何实现靶向输送TNFα以减少毒性，并展示抑制MDR所涉及的信号机制仍然是一个挑战。我们合成了一种多功能纳米系统，其中TNFα与多柔比星（Dox）负载的pH响应性介孔二氧化硅纳米颗粒（MSN）通过双功能聚乙二醇（TNFα-PEG-MSN-缩醛-Dox）共价结合，作为战胜MDR的强大设计。该纳米平台的显著特点是：1）通过精确调整结合在MSN上的TNFα浓度，我们观察到它可以产生抑制或促进肿瘤生长的相反效应；2）较高浓度的MSN-TNFα除了具有靶向肿瘤和通过外源途径诱导凋亡的多种功能外，还抑制了细胞膜蛋白P-糖蛋白（P-gp）的表达水平，后者是药物外流泵；3）MSN巨大的表面积提供了TNFα的功能化，而纳米通道则容纳了化疗药物Dox；4）通过pH依赖的缩醛键裂解，靶向的内源释放Dox通过特定的内源途径诱导凋亡；5）TNFα-PEG-MSN-缩醛-Dox（MSN-Dox-TNFα）通过解离紧密连接蛋白，能够深入3D球状瘤模型。在Dox耐药小鼠肿瘤模型中经肿瘤内给药，MSN-Dox-TNFα通过TNFα和Dox的联合表现显著呈现协同治疗效果。我们在此开发并展示了一种具有浓度调控的TNFα的多功能MSN-Dox-TNFα系统，能够废除药物耐药机制，并通过内源和外源凋亡途径显著抑制肿瘤生长，因此在MDR肿瘤治疗中具有很高的潜力。 © 2023 Hsia et al.

Cancer multidrug resistance (MDR) is an important factor that severely affects the chemotherapeutic efficacy. Among various methods to bypass MDR, usage of cytokines, such as tumor necrosis factor alpha (TNFα) is attractive, which exerts antitumor effects of immunotherapeutic response and apoptotic/proinflammatory pathways. Nevertheless, the challenges remain how to implement targeted delivery of TNFα to reduce toxicity and manifest the involved signaling mechanism that subdues MDR.We synthesized a multifunctional nanosytem, in which TNFα covalently bound to doxorubicin (Dox)-loaded pH-responsive mesoporous silica nanoparticles (MSN) through bi-functional polyethylene glycol (TNFα-PEG-MSN-Hydrazone-Dox) as a robust design to overcome MDR.The salient features of this nanoplatform are: 1) by judicious tailoring of TNFα concentration conjugated on MSN, we observed it could lead to a contrary effect of either proliferation or suppression of tumor growth; 2) the MSN-TNFα at higher concentration serves multiple functions, besides tumor targeting and inducer of apoptosis through extrinsic pathway, it inhibits the expression level of p-glycoprotein (P-gp), a cell membrane protein that functions as a drug efflux pump; 3) the enormous surface area of MSN provides for TNFα functionalization, and the nanochannels accommodate chemotherapeutics, Dox; 4) targeted intracellular release of Dox through the pH-dependent cleavage of hydrazone bonds induces apoptosis by the specific intrinsic pathway; and 5) TNFα-PEG-MSN-Hydrazone-Dox (MSN-Dox-TNFα) could infiltrate deep into the 3D spheroid tumor model through disintegration of tight junction proteins. When administered intratumorally in a Dox-resistant mouse tumor model, MSN-Dox-TNFα exhibited a synergistic therapeutic effect through the collective performances of TNFα and Dox.We hereby develop and demonstrate a multifunctional MSN-Dox-TNFα system with concentration-tailored TNFα that can abrogate the drug resistance mechanism, and significantly inhibit the tumor growth through both intrinsic and extrinsic apoptosis pathways, thus making it a highly potential nanomedicine translated in the treatment of MDR tumors.© 2023 Hsia et al.