通过柔性微针阵列集成的叉指电极装置产生电刺激用于癌症免疫治疗

Electrical stimulation induces anti-tumor immunomodulation via a flexible microneedle-array-integrated interdigital electrode

免疫疗法通过化学或生物制剂来激活免疫系统,改变了癌症治疗的传统方式.但大多数免疫类药物在肿瘤组织内的渗透性差,容易产生副作用而使疗效不尽人意.电刺激疗法是一种新颖的癌症疗法,其可以不利用化学、生物制剂产生抑癌效果,但存在操作复杂和难以制备微米级小型电刺激装置的问题.本文通过将光学3D微打印技术与化学镀工艺结合,成功制备了柔性微针阵列集成的叉指电极装置.其能够生成交变电场触发肿瘤细胞内线粒体的钙离子过载和细胞内活性氧的产生,导致损伤相关分子模式释放,从而激活免疫应答并引起肿瘤免疫原性细胞死亡.实验结果显示,本文的通电微针装置具有良好的生物安全性和全身抑瘤作用,抑制了原发肿瘤和远处肿瘤的生长以及黑色素瘤肺转移.因此,本文将电刺激与免疫疗法相结合,为无药物癌症治疗提供了新方向并为癌症治疗领域提供了创新思路.

Immunotherapy has revolutionized cancer therapy,using chemical or biological agents to reinvigorate the immune system.However,most of these agents have poor tumor penetration and inevitable side effects that complicate therapeutic outcomes.Electrical stimulation(ES)is a promising alternative therapy against cancers that does not involve chemical or biological agents but is limited in the fabrication and operation of complex micrometer-scale ES devices.Here,we present an optically microprinted flexible interdigital electrode with a gold-plated polymer microneedle array to generate alternating electric fields for cancer treatment.A flexible microneedle-array-integrated interdigital electrode(FMIE)was fabricated by combining optical 3D microprinting and electroless plating processes.FMIE-mediated ES of cancer cells induced necrotic cell death through mitochondrial Ca2+overload and increased intracellular reactive oxygen species(ROS)production.This led to the release of damage-associated molecular patterns that activated the immune response and potentiated immunogenic cell death(ICD).FMIE-based ES has an excellent safety profile and systemic anti-tumor effects,inhibiting the growth of primary and distant tumors as well as melanoma lung metastasis.FMIE-based ES-driven cancer immunomodulation provides a new pathway for drug-free cancer therapy.