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Building on this phenomenon, we developed an enzyme\u2010regulation strategy inducing LSPS of target enzymes to isolate them from substrates. As proof of concept, we created a novel D\u2010Peptide mediated Microaggregate Degradation named DPMD to capture trypsin and chymotrypsin in the seroperitoneum during postoperative pancreatic fistula (POPF). DPMD is designed with cationic and hydrophobic residues and a \u03b2\u2010sheet\u2010forming motif for specific binding. The core principle is an entropy\u2010driven peptide self\u2010assembly that sequesters these proteases from the extracellular environment. Captured enzymes form intricate peptide\u2013enzyme microaggregates, effectively segregating them from substrates. These microaggregates are readily internalized and cleared by macrophages, likely via macropinocytosis. In rat POPF models, DPMD significantly reduced pancreatic fluid leakage and inflammatory markers, improved survival, and outperformed a conventional L\u2010peptide control. Toxicity evaluations showed DPMD was well tolerated even at doses beyond therapeutic levels, underscoring its favorable safety profile. In summary, this study demonstrates a significant translational advance in POPF treatment and expands our understanding of pathogenic enzyme sequestration via LSPS, potentially opening new therapeutic avenues for a range of enzyme\u2010mediated diseases.<\/jats:p>","DOI":"10.1002\/advs.202509209","type":"journal-article","created":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T13:28:54Z","timestamp":1753277334000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Regulating Enzyme Activity via Microaggregates Mediated by Phase Separation"],"prefix":"10.1002","volume":"12","author":[{"given":"Yang","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Hepatology The Second Affiliated Hospital of Xi'an Jiaotong University  Xi'an 710004 P. R. 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