Abstract

Intracellular Ca²⁺ ions as second messenger played key role in cell behaviour, which was often overlooked in traditional antitumor treatment. Disrupting Ca²⁺ ion homeostasis by Ca²⁺ overload might switch ions signal from ‘regulating’ to ‘destroying’. Inspired by this, a biomimetic Ca²⁺ nanogenerator was constructed. Briefly, the curcumin (CUR) was loaded into mesoporous calcium carbonate nanoparticles (MCC NPs), and then coated with platelet (PLT) membrane. Upon reaching tumour cells by PLT membrane-mediated tumour targeting effect, PLT@MCC/CUR would instantaneously decompose in acidic lysosomes, concurrently accompanying with Ca²⁺ generation and CUR release. The CUR could further facilitate Ca²⁺ release from endoplasmic reticulum (ER) and inhibit Ca²⁺ efflux, aggravating Ca²⁺ overload to disrupt mitochondrial Ca²⁺ homeostasis for mitochondria apoptosis signalling pathway activation. Interestingly, such effect was ineffective in normal cells, realising the tumour-specific therapeutic therapy. Based on ions interference strategy, PLT@MCC/CUR herein offered synergistic combination of Ca²⁺ overload therapy and chemotherapy, which would pave the way towards more effective nanotherapeutics.

摘要

细胞内Ca ²⁺离子作为第二信使在细胞行为中发挥着关键作用，这在传统的抗肿瘤治疗中经常被忽视。^{通过 Ca 2+}过载破坏 Ca ²⁺离子稳态可能会将离子信号从“调节”转变为“破坏”。受此启发，构建了仿生Ca ²⁺纳米发电机。简而言之，将姜黄素（CUR）加载到介孔碳酸钙纳米颗粒（MCC NPs）中，然后用血小板（PLT）膜包被。通过PLT膜介导的肿瘤靶向作用到达肿瘤细胞后，PLT@MCC/CUR会在酸性溶酶体中瞬间分解，同时伴随Ca ²⁺的产生和CUR的释放。CUR 可以进一步促进 Ca²⁺从内质网 (ER) 释放并抑制 Ca ²⁺外流，加重 Ca ²⁺过载，破坏线粒体 Ca ²⁺稳态，从而激活线粒体凋亡信号通路。有趣的是，这种作用在正常细胞中无效，实现了肿瘤特异性治疗。基于离子干扰策略，PLT@MCC/CUR 在此提供了 Ca ²⁺超载疗法和化学疗法的协同组合，这将为更有效的纳米疗法铺平道路。