Cell membrane-coated nanoparticles target multiorgan crosstalk in cardiovascular-kidney-metabolic syndrome

Cardiovascular-Kidney-Metabolic (CKM) syndrome is a complex, integrated disorder marked by metabolic dysregulation that drives interorgan crosstalk through inflammatory, oxidative, and fibrotic pathways, ultimately leading to multiorgan dysfunction. Although organ-specific therapies confer cardioprotective and renoprotective benefits, current management remains fragmented and does not adequately address the interconnected biology of CKM syndrome. Cell membrane-coated nanoparticles (CMNPs) are a promising biomimetic platform that enables organ-selective delivery, immune evasion, and functional modulation. CMNPs are typically fabricated by extrusion, sonication, or microfluidic assembly of isolated cell membranes (e.g., from erythrocytes, macrophages, and renal tubular cells) around cores such as poly(lactic-co-glycolic acid) (PLGA), lipids, or silica. This design preserves membrane orientation and the native surface proteome, supporting immune evasion and organ-specific homing. CMNPs can carry diverse payloads, including small molecules and proteins, and release them in response to pH, reactive oxygen species (ROS), or enzymatic cues, thereby enabling coordinated interventions across CKM-related organs. This review summarizes recent advances in CMNPs for CKM-relevant multiorgan crosstalk, emphasizing membrane source-dependent functions, design strategies, and mechanisms underlying metabolic regulation, vascular protection, and renal targeting. We highlight hybrid membrane engineering and stimulus-responsive technologies as potential routes to synergistic multiorgan effects and discuss key translational challenges, including biocompatibility, scalable manufacturing, standardization, immunogenicity assessment, membrane sourcing, and regulatory considerations. Evidence from animal models suggests plausible clinical trajectories, particularly for combination strategies that suppress inflammatory signaling, reduce fibrotic remodeling, and restore metabolic homeostasis across organs. A forward-looking roadmap underscores the need to develop safe, reproducible CMNP platforms for precise multiorgan interventions in CKM subpathologies and calls for integrating CMNP-based approaches into existing CKM management frameworks, supported by systematic preclinical-to-clinical bridging studies to accelerate translation. STATEMENT OF SIGNIFICANCE: This review demonstrates the transformative potential of cell membrane-coated nanoparticles (CMNPs) as a biomimetic platform to address the complex Cardiovascular-Kidney-Metabolic (CKM) syndrome. By integrating organ-selective targeting with coordinated modulation of shared pathogenic pathways, CMNPs offer a unified approach to the interorgan crosstalk that underpins CKM, a domain inadequately managed by conventional organ-centric therapies. Although CMNPs have shown efficacy in isolated metabolic, cardiovascular, or renal disease models, there remains a critical gap: to date, almost no studies or comprehensive reviews have examined CMNPs in CKM or other multi-system diseases. The dual capabilities of CMNPs-membrane-mediated immune evasion and enhanced tissue interactions-enable simultaneous metabolic regulation, vascular protection, and renal targeting within a single platform. This integrated strategy could redefine CKM management and advance precision nanomedicine, with meaningful implications for patient outcomes across multiple organ systems.