Metal-Organic Framework-Based Nanomedicine for Sepsis Therapy: From Microenvironment Regulation to Precision Therapeutic Strategies.

Sepsis is a complex and life-threatening syndrome driven by a dysregulated host response to infection, involving persistent oxidative stress, excessive inflammation, immune paralysis, metabolic disturbance, and progressive organ dysfunction. Although substantial advances have been achieved in supportive therapies, effective treatments capable of modifying the underlying pathological processes remain lacking. The major challenge lies in the highly interconnected nature of the septic microenvironment, where oxidative stress, inflammatory signaling, and immune imbalance form a dynamic pathological network that conventional single-target strategies cannot effectively correct. Metal-organic frameworks (MOFs) are crystalline porous materials assembled from metal nodes (eg, Fe, Cu, Ce, Mn, and Zn) and organic ligands; owing to their highly tunable structures, catalytic properties, and versatile cargo-loading capabilities, have recently emerged as promising nanoplatforms for addressing complex biological disorders. In sepsis therapy, MOFs provide unique opportunities not only for reactive oxygen species regulation and anti-inflammatory intervention but also for targeted drug delivery, immune modulation, pathogen/endotoxin neutralization, and integrated diagnosis and treatment. Key functionalization strategies reviewed here include enzyme-mimetic (nanozyme) catalysis, biomimetic membrane coating and active targeting, stimuli-responsive (pH/ROS) delivery, genetic cargo delivery, and theranostic integration. However, a systematic understanding of how MOF-based nanomedicine reshapes the multifaceted septic microenvironment remains insufficient. In this review, we summarize recent advances in MOF-based strategies for sepsis management, focusing on their roles in regulating oxidative stress, inflammatory responses, immune dysfunction, and metabolic abnormalities. We discuss the design principles of MOF nanoplatforms, including enzyme-mimetic catalysis, stimuli-responsive delivery, immune regulation, and theranostic applications. Furthermore, we highlight current challenges associated with biosafety (including the fate of released metal ions), pharmacokinetics, scalable fabrication, and clinical translation, and propose future perspectives involving precision nanomedicine and intelligent MOF design. This review aims to provide a comprehensive understanding of MOF-enabled regulation of septic pathological networks and to inspire the development of next-generation nanotherapeutic approaches for sepsis treatment.