TY - JOUR
T1 - A programmable protease-based protein secretion platform for therapeutic applications
AU - Wang, Xinyi
AU - Kang, Liping
AU - Kong, Deqiang
AU - Wu, Xin
AU - Zhou, Yang
AU - Yu, Guiling
AU - Dai, Di
AU - Ye, Haifeng
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2023.
PY - 2024/4
Y1 - 2024/4
N2 - Cell-based therapies represent potent enabling technologies in biomedical science. However, current genetic control systems for engineered-cell therapies are predominantly based on the transcription or translation of therapeutic outputs. Here we report a protease-based rapid protein secretion system (PASS) that regulates the secretion of pretranslated proteins retained in the endoplasmic reticulum (ER) owing to an ER-retrieval signal. Upon cleavage by inducible proteases, these proteins are secreted. Three PASS variants (chemPASS, antigenPASS and optoPASS) are developed. With chemPASS, we demonstrate the reversal of hyperglycemia in diabetic mice within minutes via drug-induced insulin secretion. AntigenPASS-equipped cells recognize the tumor antigen and secrete granzyme B and perforin, inducing targeted cell apoptosis. Finally, results from mouse models of diabetes, hypertension and inflammatory pain demonstrate light-induced, optoPASS-mediated therapeutic peptide secretion within minutes, conferring anticipated therapeutic benefits. PASS is a flexible platform for rapid delivery of therapeutic proteins that can facilitate the development and adoption of cell-based precision therapies. (Figure presented.)
AB - Cell-based therapies represent potent enabling technologies in biomedical science. However, current genetic control systems for engineered-cell therapies are predominantly based on the transcription or translation of therapeutic outputs. Here we report a protease-based rapid protein secretion system (PASS) that regulates the secretion of pretranslated proteins retained in the endoplasmic reticulum (ER) owing to an ER-retrieval signal. Upon cleavage by inducible proteases, these proteins are secreted. Three PASS variants (chemPASS, antigenPASS and optoPASS) are developed. With chemPASS, we demonstrate the reversal of hyperglycemia in diabetic mice within minutes via drug-induced insulin secretion. AntigenPASS-equipped cells recognize the tumor antigen and secrete granzyme B and perforin, inducing targeted cell apoptosis. Finally, results from mouse models of diabetes, hypertension and inflammatory pain demonstrate light-induced, optoPASS-mediated therapeutic peptide secretion within minutes, conferring anticipated therapeutic benefits. PASS is a flexible platform for rapid delivery of therapeutic proteins that can facilitate the development and adoption of cell-based precision therapies. (Figure presented.)
UR - https://www.scopus.com/pages/publications/85174626026
U2 - 10.1038/s41589-023-01433-z
DO - 10.1038/s41589-023-01433-z
M3 - 文章
C2 - 37872400
AN - SCOPUS:85174626026
SN - 1552-4450
VL - 20
SP - 432
EP - 442
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 4
ER -
