Emerging strategies against accelerated blood clearance phenomenon of nanocarrier drug delivery systems

Nanocarrier drug delivery systems (NDDS) have gained momentum in the field of anticancer or nucleic acid drug delivery due to their capacity to aggrandize the targeting efficacy and therapeutic outcomes of encapsulated drugs. A disadvantage of NDDS is that repeated administrations often encounter an obstacle known as the "accelerated blood clearance (ABC) phenomenon". This phenomenon results in the rapid clearance of the secondary dose from the bloodstream and markedly augmented liver accumulation, which substantially undermines the accurate delivery of drugs and the therapeutic effect of NDDS. Nevertheless, the underlying mechanism of this phenomenon has not been elucidated and there is currently no effective method for its eradication. In light of the above, the aim of this review is to provide a comprehensive summary of the underlying mechanism and potential countermeasures of the ABC phenomenon, with a view to rejuvenating both the slow-release property and expectation of NDDS in the clinic. In this paper, we innovatively introduce the pharmacokinetic mechanism of ABC phenomenon to further elucidate its occurrence mechanism after discussing its immunological mechanism, which provides a new direction for expanding the mechanistic study of ABC phenomenon. Whereafter, we conducted a critical conclusion of potential strategies for the suppression or prevention of the ABC phenomenon in terms of the physical and structural properties, PEG-lipid derivatives, dosage regimen and encapsulated substances of nanoformulations, particularly covering some novel high-performance nanomaterials and mixed modification methods. Alternatively, we innovatively propose a promising strategy of applying the characteristics of ABC phenomenon, as the significantly elevated hepatic accumulation and activated CYP3A1 profile associated with the ABC phenomenon are proved to be conducive to enhancing the efficacy of NDDS in the treatment of hepatocellular carcinoma. Collectively, this review is instructive for surmounting or wielding the ABC phenomenon and advancing the clinical applications and translations of NDDS.