Recent advances in protein modification-enabled potential therapeutics.

The field of protein therapeutics has evolved from native biologics to precision-engineered multi-functional therapeutic agents, overcoming inherent limitations such as structural instability, rapid clearance, and immunogenicity. While early strategies, including PEGylation and albumin fusion, and the emergence of antibody-drug conjugates (ADCs), have demonstrated clinical value, challenges remain in improving the site-specificity of modifications, suppressing structural heterogeneity, adjusting linker stability, and broadening payload diversity for protein therapeutics. Recent advances in bioconjugation techniques, such as chemoselective reactions, enzymatic labeling, glycan engineering, and genetic code expansion, now enable more site-specific and homogeneous modifications, achieving enhancements in batch consistency, controlled payload release, and multi-functionality. This review highlights key developments over the past two years across three categories of modified protein therapeutics: ADCs, cytokines, and proximity-enabled covalent therapeutics. Looking forward, we outline future directions focused on scalable site-specific platforms, immunogenicity management, and delivery optimization, increasingly propelled by artificial intelligence-aided protein design and reaction manipulation.