Red blood cells (RBCs) and RBC membrane-derived nanoparticles have been historically developed as bioinspired drug delivery systems to combat the issues of premature clearance, toxicity, and immunogenicity of synthetic nanocarriers. RBC-based delivery systems possess characteristics including biocompatibility, biodegradability, and long circulation time, which make them suited for systemic administration. Therefore, they have been employed in designing optimal drug formulations in various preclinical models and clinical trials to treat a wide range of diseases. In this review, we provide an overview of the biology, synthesis, and characterization of drug delivery systems based on RBCs and their membrane including whole RBCs, RBC membrane-camouflaged nanoparticles, RBC-derived extracellular vesicles, and RBC hitchhiking. We also highlight conventional and latest engineering strategies, along with various therapeutic modalities, for enhanced precision and effectiveness of drug delivery. Additionally, we focus on the current state of RBC-based therapeutic applications and their clinical translation as drug carriers, as well as discussing opportunities and challenges associated with these systems.

Blood cell‐derived extracellular vesicles (BCEVs) and lipoproteins are the major circulating nanoparticles in blood that play an important role in intercellular communication. They have attracted significant interest for clinical applications, given their endogenous characteristics which make them stable, biocompatible, well tolerated, and capable of permeating biological barriers efficiently. In this review, we describe the basic characteristics of BCEVs and lipoproteins and summarize their implications in both physiological and pathological processes. We also outline well accepted workflows for the isolation and characterization of these circulating nanoparticles. Importantly, we highlight the latest progress and challenges associated with the use of circulating nanoparticles as diagnostic biomarkers and therapeutic interventions in multiple diseases. We spotlight novel engineering approaches and designs to facilitate the development of these nanoparticles by enhancing their stability, targeting capability, and delivery efficiency. Therefore, the present work provides a comprehensive overview of composition, biogenesis, functions, and clinical translation of circulating nanoparticles from the bench to the bedside.

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