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This challenge is well exemplified by reconstituted high\u2010density lipoprotein (rHDL), a clinically advanced HDL mimetic and representative biomimetic drug delivery platform. Here, guided by a pathology\u2010informed identification\u2010design\u2010evaluation\u2010validation workflow, we identified representative sepsis\u2010relevant dysfunction liabilities of HDL\u2010based systems under pathology\u2010relevant conditions and designed an adaptive engineered guard for inflammatory stress (AEGIS) strategy to rescue rHDL function. AEGIS integrates triphenylphosphine\u2010modified ceria nanozyme\u2010celastrol coordination complex (TCe\u2013C) into rHDL to form TCe\u2010C@rHDL, enabling carrier protection, decoupling disease\u2010driven damage from dysfunction, and preserving HDL\u2010intrinsic routing for hierarchical cytoplasmic and mitochondrial delivery. Across multiple evaluation models, including inflammatory biochemical challenges, patient serum under shear flow, and inflammatory animal settings, TCe\u2010C@rHDL consistently preserved biomimetic function better than a clinical\u2010stage CER\u2010001 mimetic. This performance was further validated by therapeutic efficacy in vivo, restoring 90% survival in LPS\u2010induced systemic inflammation versus 40% for the CER\u2010001 mimetic, and improving survival to 80% in the CLP model when combined with antibiotics versus 40% for antibiotics alone. Collectively, this work establishes a paradigm for next\u2010generation biomimetic systems that remain functional under pathological stress.<\/jats:p>","DOI":"10.1002\/advs.77714","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T04:25:17Z","timestamp":1789100717000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond Biomimetics: Pathology\u2010Informed Engineering Rescues Reconstituted HDL From Inflammatory Dysfunction for Sepsis Immunotherapy"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-8320-3613","authenticated-orcid":false,"given":"Han","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics China Pharmaceutical University  Nanjing Jiangsu People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of 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