A biomimetic SPARC platform coupling adaptor recruitment and BRS-Lck condensation for enhanced NK/T cell combination therapy
- 1Institute of Biophysics, Chinese Academy of Sciences
Abstract
Immune cell engineering has proven to be a promising therapeutic strategy for cancers and autoimmune diseases. Compared to classical CAR therapies, engineered T cells with modified TCRs (such as STAR-T and TRuC-T) exhibit lower tonic signaling and higher persistence. Inspired by this, we developed novel Synthetic Parallel Antigen Receptor Complexes (SPARC) based on the NK cell receptor 1 (NCR1) and the TCR chain. These SPARCs can recognize target cells via engineered extracellular domains and transduce signals by recruiting endogenous adaptor proteins (CD3{zeta}/FcR{gamma}). In NK cells,SPARCs confer high antigen specificity against lymphoma and enables NK cells to specifically recognize and kill tumor cells. Mechanistically, the cytoplasmic domain of NCR1 forms condensates with Lck kinase through two conserved basic-rich sequences (BRS), thereby promoting receptor clustering and enhancing NK cell cytotoxicity. Our findings indicate that SPARCs can also be applied to other immune cells expressing CD3{zeta} and FcR{gamma}. Incorporation of costimulatory domains further improves the performance of SPARCs. Furthermore, combining SPARC-engineered T cells and NK cells showed superior efficacy compared to either cell type alone. This biomimetic design preserves low basal signaling, overcomes the recognition limitations of endogenous receptors, and provides a versatile platform for engineering other membrane complexes.
Related
- Phosphorylation-tuned condensation links HCMV tegument assembly to membrane recruitment
- A multivalent docking platform and Rcn1-mediated inhibition control the extent of calcineurin recruitment to the cell division site for the dephosphorylation of multiple cytokinetic proteins
- Multilayer and Biomimetic Polycaprolactone/Uterine ECM Scaffold for Uterine Tissue Engineering and Anti-Adhesion Barrier Applications via 3D-Printing Near-Field Melt Electrowriting
- HelixWings enables AI-driven enzyme engineering for biomimetic cofactor utilization
- Fibronectin-Assisted Coating of Low-Molecular-Weight Fucoidan Creates a Biomimetic Interface for Endothelialization of Cobalt-Chromium Stents
BibTeX
@misc{wang2026biomimetic,
title = {{A biomimetic SPARC platform coupling adaptor recruitment and BRS-Lck condensation for enhanced NK/T cell combination therapy}},
author = {Q. Wang and S. Wu and Y. Qiu and J. Lou and C. Lou and H. Chen},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.02.763574},
url = {https://www.biorxiv.org/content/10.64898/2026.11.02.763574v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - A biomimetic SPARC platform coupling adaptor recruitment and BRS-Lck condensation for enhanced NK/T cell combination therapy
AU - Q. Wang
AU - S. Wu
AU - Y. Qiu
AU - J. Lou
AU - C. Lou
AU - H. Chen
PY - 2026
DA - 2026/11/02
PB - bioRxiv
DO - 10.64898/2026.11.02.763574
UR - https://www.biorxiv.org/content/10.64898/2026.11.02.763574v1
AB - Immune cell engineering has proven to be a promising therapeutic strategy for cancers and autoimmune diseases. Compared to classical CAR therapies, engineered T cells with modified TCRs (such as STAR-T and TRuC-T) exhibit lower tonic signaling and higher persistence. Inspired by this, we developed novel Synthetic Parallel Antigen Receptor Complexes (SPARC) based on the NK cell receptor 1 (NCR1) and the TCR chain. These SPARCs can recognize target cells via engineered extracellular domains and transduce signals by recruiting endogenous adaptor proteins (CD3{zeta}/FcR{gamma}). In NK cells,SPARCs confer high antigen specificity against lymphoma and enables NK cells to specifically recognize and kill tumor cells. Mechanistically, the cytoplasmic domain of NCR1 forms condensates with Lck kinase through two conserved basic-rich sequences (BRS), thereby promoting receptor clustering and enhancing NK cell cytotoxicity. Our findings indicate that SPARCs can also be applied to other immune cells expressing CD3{zeta} and FcR{gamma}. Incorporation of costimulatory domains further improves the performance of SPARCs. Furthermore, combining SPARC-engineered T cells and NK cells showed superior efficacy compared to either cell type alone. This biomimetic design preserves low basal signaling, overcomes the recognition limitations of endogenous receptors, and provides a versatile platform for engineering other membrane complexes.
ER -