Shaping mesenchymal stem cell fate with a two-dimensional covalent triazine framework for calmodulin modulation.

Abstract

Calmodulin (CaM) is a central calcium sensor and signaling hub that critically governs stem cell fate. However, directly intracellular modulation of CaM remains challenging due to its activity is tightly coupled to finely balanced calcium homeostasis, and conventional chemicals or biomaterials have limited ability to access or target it. Here, we introduce a novel two-dimensional, porous, covalent triazine-based framework, CTF-Ca, synthesized under ambient conditions, that offers a new strategy for intracellular CaM regulation. Unlike conventional approaches, CTF-Ca bypasses membrane calcium channels, enabling direct calcium influx into mesenchymal stem cells (MSCs) and triggering robust, sustained activation of the Ca²⁺/CaM signaling pathway. This activation markedly enhances osteogenic differentiation in MSCs. Remarkably, CTF-Ca also compensates for suppressed CaM function, restoring osteogenic potential in MSCs even under CaM-inhibited conditions. This compensatory effect was further demonstrated in C2C12 myogenic progenitor cells, a skeletal muscle model characterized with high endogenous CaM expression, where CTF-Ca rescued myotube formation in CaM deficient cells, underscoring its broad applicability. Together, these findings establish CTF-Ca as an effective 2D material for direct intracellular modulation of CaM, offers a promising new tool for regulating stem and progenitor cells fate.