Repurposing salicylic acid as a versatile inducer of proximity.

Chemically induced proximity (CIP) has remarkably advanced the development of molecular and cellular therapeutics. To maximize therapeutic potential, there is a pressing need to expand the repertoire of CIP systems of translational values, favoring chemical ligands that are cost-effective, structurally simple, biocompatible, reversible and have minimal side effects. Here, we present a salicylic acid (SA)-mediated binary association system (SAMBA), evolved from a tobacco SA receptor, that enables rapid protein-protein heterodimerization in response to SA or aspirin after hydrolysis. We demonstrate the broad applicability of SAMBA in various biological contexts, including SA-dependent reprogramming of a protein-based reaction-diffusion system, graded gating of calcium channels, inducible initiation of receptor tyrosine kinase-mediated signaling and gene expression, and tunable activation of chimeric antigen receptor T cells. Our work establishes SAMBA as a versatile chemogenetic platform that allows temporal control of biological processes and therapeutic cells both in vitro and in vivo.