2. Academic Validation
  3. Engineered peripheral CD4 T cells delivery across the BBB promote intracerebral Treg conversion unleashes microglial phagocytotic activity for Alzheimer's disease treatment

Engineered peripheral CD4 T cells delivery across the BBB promote intracerebral Treg conversion unleashes microglial phagocytotic activity for Alzheimer's disease treatment

  • Biomaterials. 2026 Feb:325:123574. doi: 10.1016/j.biomaterials.2025.123574.
Zejie Zuo 1,  Zecong Xiao 2,  Liying Zhang 1,  Shaohui Deng 3,  Xiaofei He 1,  Yating Mu 1,  Pingyi Wang 1,  Yifeng Feng 1,  Zemeng Wang 4,  Shiyin Li 1,  Xiaofeng Yang 1,  Jinghui Xu 1,  Kaihua Guo 4,  Wenhai Guo 5,  Xintao Shuai 6,  Xiquan Hu 7,  Haiqing Zheng 8
Affiliations

Affiliations

  • 1 Department of Rehabilitation Medicine, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, China.
  • 2 Nanomedicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, China.
  • 3 PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, 510275, China.
  • 4 Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
  • 5 Department of Traditional Chinese Medicine, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, China.
  • 6 Nanomedicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, China. Electronic address: shuaixt@mail.sysu.edu.cn.
  • 7 Department of Rehabilitation Medicine, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, China. Electronic address: huxiquan@mail.sysu.edu.cn.
  • 8 Department of Rehabilitation Medicine, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, China. Electronic address: zhenghq2@mail.sysu.edu.cn.
PMID: 40763582 DOI: 10.1016/j.biomaterials.2025.123574
Abstract

Alzheimer's disease (AD) affects thirty million individuals worldwide, but a viable treatment has yet to be identified. During disease progression, peripheral immune cells, including peripheral T cells, infiltrate the brain. Although CD4+ regulatory T cells have been demonstrated to exhibit neuroprotective efficacy in AD, the precise roles of these cells in the brain remain elusive. Here, we report that β-amyloid (Aβ) 1-42 antigen-specific CD4+ T cells spontaneously cross the blood-brain barrier (BBB) into the brain in an APP/PS1 mouse model. To promote parenchymal Treg conversion from infiltrated CD4+ T cells and minimize the perturbations of the brain microenvironment, we engineered an Aβ1-42 antigen-specific CD4+ T cell-based nanodelivery system to release the compound AS2863619, a CDK8/19 inhibitor (eTc-AS), which can bypass the BBB and selectively induce the conversion of CD4+ T cells into Treg cells within the brain region. These cells demonstrated notable pathological amelioration in APP/PS1 mice, in part by interacting with microglia or recruited macrophage via PD-L1/PD-1 signaling. Our study reveals valuable engineered T cell therapies and suggests an immune checkpoint mechanism underlying the neuroprotective function of the Treg-microglia like cell interplay in AD.

Keywords

Alzheimer's disease; Blood-brain barrier; Engineered T cells; Microglia; Phagocytosis; T regulatory cells; β-amyloid.

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