Beyond Biomimetics: Pathology-Informed Engineering Rescues Reconstituted HDL From Inflammatory Dysfunction for Sepsis Immunotherapy.

Biomimetic therapies hold great promise for treating intractable diseases, yet their translation is often hindered by dysfunction-the loss of intended biological function upon exposure to pathological microenvironments. This challenge is well exemplified by reconstituted high-density lipoprotein (rHDL), a clinically advanced HDL mimetic and representative biomimetic drug delivery platform. Here, guided by a pathology-informed identification-design-evaluation-validation workflow, we identified representative sepsis-relevant dysfunction liabilities of HDL-based systems under pathology-relevant conditions and designed an adaptive engineered guard for inflammatory stress (AEGIS) strategy to rescue rHDL function. AEGIS integrates triphenylphosphine-modified ceria nanozyme-celastrol coordination complex (TCe-C) into rHDL to form TCe-C@rHDL, enabling carrier protection, decoupling disease-driven damage from dysfunction, and preserving HDL-intrinsic 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-C@rHDL consistently preserved biomimetic function better than a clinical-stage CER-001 mimetic. This performance was further validated by therapeutic efficacy in vivo, restoring 90% survival in LPS-induced systemic inflammation versus 40% for the CER-001 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-generation biomimetic systems that remain functional under pathological stress.