Wang Danyu, Yi Hua, Zhang Jiali, Huang Mengyu, Qiu Yue, Wang Yang, Chen Peiru, Liu Chan, Xu Tingyi, Yang Qiuxia, Yang Kuikun, Guo Zhenzhen, Zhang Kaixiang
School of Pharmaceutical Sciences, State Key Laboratory of Metabolic Dysregulation and Prevention and Treatment of Esophageal Cancer, State Key Laboratory of Antiviral Drugs, Tianjian Laboratory of Advanced Biomedical Sciences, Pingyuan Laboratory, Zhengzhou University, Zhengzhou, Henan 450001, China.
School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang 150080, P. R. China.
J Am Chem Soc. 2026 Feb 18;148(6):6057-6071. doi: 10.1021/jacs.5c16425. Epub 2026 Feb 4.
Adoptive natural killer (NK) cell therapy for solid tumors faces critical challenges, including tumor antigen heterogeneity, impaired tumor infiltration, and suboptimal activation imposed by the immunosuppressive microenvironment. Here we developed an engineered nanoplatform featuring transmembrane DNA nanochannel-engineered artificial receptors (NCAR) to direct NK cells against solid tumors through two synergistic mechanisms: 1) Tumor Microenvironment (TME) Reprogramming: leveraging cholesterol-mediated insertion, NCAR incorporates into tumor membranes to disrupt phospholipid bilayers, inducing immunogenic cell death with the release of damage-associated molecular patterns (DAMPs; e.g., HMGB1, CRT), which remodels immunosuppression TME and recruits/activates NK cells. 2) Precision Targeting: NCAR forms programmable synthetic immune synapses with DNA nanoartificial ligands (NAL) engineered on NK cells via base-pairing. This antigen-independent assembly network establishes a universal membrane interface, enabling sustained tumor-targeted NK cell activation. The dual-component system enables sustained intratumoral accumulation of NK cells (>96 h), with a 15.1-fold increase in activated NKP46GZB NK cells compared to controls. By bridging DNA nanotechnology with cell immunotherapy, our nanoplatform provides a universal strategy for navigating tumor-immune interactions, addressing key limitations of adoptive NK cell immunotherapy in solid tumors.
实体瘤的过继性自然杀伤（NK）细胞疗法面临着严峻挑战，包括肿瘤抗原异质性、肿瘤浸润受损以及免疫抑制微环境导致的激活不足。在此，我们开发了一种工程化纳米平台，其具有跨膜DNA纳米通道工程化人工受体（NCAR），可通过两种协同机制引导NK细胞靶向实体瘤：1）肿瘤微环境（TME）重编程：利用胆固醇介导的插入作用，NCAR整合到肿瘤细胞膜中以破坏磷脂双层，通过释放损伤相关分子模式（DAMPs；例如，HMGB1、CRT）诱导免疫原性细胞死亡，从而重塑免疫抑制性TME并招募/激活NK细胞。2）精准靶向：NCAR通过碱基配对与工程化在NK细胞上的DNA纳米人工配体（NAL）形成可编程的合成免疫突触。这种不依赖抗原的组装网络建立了一个通用的膜界面，能够持续激活靶向肿瘤的NK细胞。该双组分系统使NK细胞能够在肿瘤内持续积聚（>96小时），与对照组相比，活化的NKP46GZB NK细胞增加了15.1倍。通过将DNA纳米技术与细胞免疫疗法相结合，我们的纳米平台提供了一种通用策略来调控肿瘤-免疫相互作用，解决了实体瘤过继性NK细胞免疫疗法的关键局限性。
