Biomimetic approaches against accelerated blood clearance (ABC) phenomenon of nanoparticulate drug delivery systems.

Surface coating of nanocarriers with poly(ethylene glycol) (PEG) has been widely used as a strategy for prolonging the circulation time of nanocarriers. However, the ABC phenomenon presents a significant challenge for PEGylated nanocarriers, causing rapid clearance of repeated doses and undermining therapeutic efficacy. Biomimetic strategies offer promising solutions by leveraging natural biological interactions to evade immune recognition and prolong circulation. In this review, we present biomimetic approaches, including cell membrane coating, cellular hitchhiking, exosomes, pathogen mimicking, and natural polymers, as potential countermeasures to the ABC phenomenon associated with PEGylated nanocarriers. Cell membrane-coated nanoparticles combine synthetic cores with cell-derived membrane proteins to replicate native cell surfaces, facilitating immune evasion and targeted delivery. Exosomes, which possess low immunogenicity and membrane fusion capabilities, can bypass lysosomal degradation and enhance delivery compared to synthetic carriers. Cellular hitchhiking utilizes endogenous cells as "Trojan horses" to transport nanoparticles, leveraging cellular motility to evade phagocytosis while improving site-specific accumulation. Pathogen-mimicking strategies incorporate viral fusion proteins or lactic acid bacteria (LAB), which have been safely used by humans for centuries, to enhance cellular uptake and promote endosomal escape. Natural polymers, such as proteins and polysaccharides, provide biocompatible coatings that reduce opsonization while enabling controlled drug release. Collectively, this review presents nature-inspired strategies for mitigating the ABC phenomenon and enhancing the therapeutic efficacy of nanoparticulate drug delivery systems.