β2-microglobulin (β2m), a host immune protein, selectively blocks curli protein assembly in E. coli, preventing biofilm formation without affecting bacterial growth. The mechanism involves β2m binding to curli fibers during their assembly process, disrupting the structural foundation necessary for bacterial communities to establish protective matrices. This represents a previously unknown antimicrobial function for β2m beyond its established role in antigen presentation. The discovery illuminates how the innate immune system may naturally combat bacterial persistence through structural interference rather than direct killing. This finding could reshape therapeutic approaches to biofilm-associated infections, which affect millions globally and contribute significantly to antibiotic resistance. Unlike broad-spectrum antibiotics that select for resistant strains, β2m's targeted disruption of biofilm architecture offers a precision approach that leaves bacterial viability intact while dismantling their protective communities. The research suggests potential for developing β2m-based therapies or synthetic analogs that could complement existing treatments. However, translation to clinical applications requires validation in complex infection models and assessment of whether pathogenic bacteria might evolve mechanisms to circumvent this host defense strategy.