Locking in stability: a biocompatible calcium-squarate framework for protein preservation under extreme stress

Protein therapeutics are highly vulnerable to thermal and mechanical stress, resulting in denaturation and aggregation that complicate storage and transportation. Here, we demonstrate that the calcium-squarate metal-organic framework UTSA-280 provides a chemically rigid and biocompatible confinement matrix for insulin stabilization. Insulin is quantitatively encapsulated via in situ mineralization while preserving the crystallinity, morphology, and coordination environment of the framework. Structural and thermal analyses reveal that crystalline confinement within UTSA-280 significantly enhances resistance to heat, agitation, and freeze-thaw stress compared to free insulin. Unlike zinc- or zirconium-based MOFs, UTSA-280 exploits endogenous Ca²⁺ coordination to achieve non-destructive host-guest integration. These findings establish calcium-based MOFs as a promising chemical platform for stress-resilient stabilization of protein therapeutics.