<br>负载硼替佐米的免疫脂质体对抗表达 CD44 的巨噬细胞：炎症消退的相互作用,Nanoscale

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负载硼替佐米的免疫脂质体对抗表达 CD44 的巨噬细胞：炎症消退的相互作用
Nanoscale ( IF 5.8 ) Pub Date : 2024-02-06 , DOI: 10.1039/d4nr00137k
Simran Nasra ₁ , Haly Shukla ₁ , Milonee Patel ₁ , Ashutosh Kumar ₁

Affiliation

巨噬细胞驱动的炎症是一系列病理状况的核心参与者，包括自身免疫性疾病、各种癌症以及类风湿性关节炎等慢性炎症状态。针对巨噬细胞行为而定制的治疗策略因其有效缓解慢性炎症的潜力而引起了极大的兴趣。在这项研究中，我们介绍了一种开创性的治疗方法，利用携带硼替佐米的专门的 CD44 靶向免疫脂质体来解决细胞水平的炎症，该策略的意义在于其精确性。 Bortezomib 对蛋白酶体的抑制会干扰控制 NFκB 激活的微调机制，最终导致炎症反应下调。在进行计算对接证明其与蛋白酶体分子具有强结合亲和力后，所得纳米结构显示出144.26±74.4 nm的流体动力学尺寸和准球形形态。此外，纳米结构确保了最短 30 天的保质期，旨在实现具有实际寿命的靶向递送。免疫脂质体内化后，与 CD44 受体的相互作用表现出下游信号传导事件。这包括 Jun 氨基末端激酶 1/2 (JNK1/2) 和细胞外信号调节激酶 (ERK) 通路的激活。 JNK1/2的激活可能导致线粒体促凋亡因子的释放，触发内在的凋亡途径并激活caspases，这从凋亡基因和蛋白表达水平得到了证实。这种疗法针对巨噬细胞的精确靶向和抗炎作用有望对多种炎症性疾病进行治疗干预，为对抗过度炎症的精准医学提供了新途径。

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Bortezomib-loaded immunoliposomes against CD44 expressing macrophages: an interplay for inflammation resolution

Macrophage-driven inflammation is the central player in a range of pathological conditions, comprising autoimmune disorders, various cancers, as well as chronic inflammatory states like rheumatoid arthritis. Therapeutic strategies tailored to specifically target macrophage behavior have acquired substantial interest for their potential to alleviate chronic inflammation effectively. In this study, we introduce a pioneering therapeutic approach utilizing specialized CD44-targeted immunoliposomes carrying bortezomib to address inflammation at the cellular level and the significance of this strategy lies in its precision nature. Bortezomib's inhibition of the proteasome interferes with the finely-tuned mechanism that controls NFκB activation, ultimately leading to a downregulation of the inflammatory response. After performing computational docking demonstrating its strong binding affinity to the proteasome molecule, the resulting nano-construct displayed a hydrodynamic size of 144.26 ± 74.4 nm and a quasi-spherical morphology. Moreover, the nano-construct ensured a minimum shelf-life of 30 days, aiming for targeted delivery with practical longevity. Upon internalization of immunoliposomes, the interaction with CD44 receptors exhibited downstream signaling events. This included the activation of Jun amino-terminal kinases 1/2 (JNK1/2) and the extracellular-signal-regulated kinases (ERK) pathway. JNK1/2 activation may lead to the release of mitochondrial pro-apoptotic factors, triggering the intrinsic apoptotic pathway and activation of caspases, which was confirmed from the level of apoptotic gene and protein expression. The precise targeting and anti-inflammatory action of this therapy against macrophages hold promise for therapeutic interventions in a wide range of inflammatory conditions, offering a novel avenue for precision medicine in the battle against excessive inflammation.

更新日期：2024-02-06

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