Decoding Outer Membrane β-Barrels: From Structural Curiosity to Engineered Nanotherapeutics

Transmembrane β-barrel outer membrane proteins or OMPs are specialized molecular gatekeepers embedded in the outer membranes of Gram-negative bacteria, mitochondria, and chloroplast. These proteins orchestrate a wide spectrum of biological functions, serving as (i) sensors transferring signals uni- or bidirectionally, (ii) channels conducting small metabolites to transporters of large proteins, (iii) adhesins and receptors for communication, and (iv) chaperones for protein and organelle biogenesis, and they are biologically important molecular scaffolds that regulate cellular homeostasis and decide the fate of the organism. OMPs have emerged as structurally versatile and functionally dynamic entities important for future therapeutics and precision interventions. Scientific and technological advances (cryo-EM, NMR, MD simulations, AlphaFold) have enhanced our understanding of the structures, biochemical functions, and interactomes of OMPs, revealing unprecedented insights on their molecular biogenesis and energetics, structural organization and dynamic regulation, and function in vivo. This review integrates the discovery and early studies of OMP structures and folding energy landscapes with their organizational, mechanistic, and functional diversity. Insights from rational engineering of β-barrels highlight their application in biosensing, drug delivery, diagnostics, synthetic biology, and nanomedicine. These developments will transform our understanding of OMPs from structural curiosity to precision biomolecular design and next-generation nanotherapeutics.