Biopharmaceuticals have emerged to play a vital role in disease treatment and have shown promise in the rapidly expanding pharmaceutical market due to their high specificity and potency. However, the delivery of these biologics is hindered by various physiological barriers, owing primarily to the poor cell membrane permeability, low stability, and increased size of biologic agents. Since many biological drugs are intended to function by interacting with intracellular targets, their delivery to intracellular targets is of high relevance. In this review, the authors summarize and discuss the use of nanocarriers for intracellular delivery of biopharmaceuticals via endosomal escape and, especially, the routes of direct cytosolic delivery by means including the caveolae‐mediated pathway, contact release, intermembrane transfer, membrane fusion, direct translocation, and membrane disruption. Strategies with high potential for translation are highlighted. Finally, the authors conclude with the clinical translation of promising carriers and future perspectives.

Atherosclerosis (AS) is a lipid-driven chronic inflammatory disease occurring at the arterial subendothelial space. Macrophages play a critical role in the initiation and development of AS. Herein, targeted codelivery of anti-miR 155 and anti-inflammatory baicalein is exploited to polarize macrophages toward M2 phenotype, inhibit inflammation and treat AS. The codelivery system consists of a carrier-free strategy (drug-delivering-drug, DDD), fabricated by loading anti-miR155 on baicalein nanocrystals, named as baicalein nanorods (BNRs), followed by sialic acid coating to target macrophages. The codelivery system, with a diameter of 150 nm, enables efficient intracellular delivery of anti-miR155 and polarizes M1 to M2, while markedly lowers the level of inflammatory factors in vitro and in vivo . In particular, intracellular fate assay reveals that the codelivery system allows for sustained drug release over time after internalization. Moreover, due to prolonged blood circulation and improved accumulation at the AS plaque, the codelivery system significantly alleviates AS in animal model by increasing the artery lumen diameter, reducing blood pressure, promoting M2 polarization, inhibiting secretion of inflammatory factors and decreasing blood lipids. Taken together, the codelivery could potentially be used to treat vascular inflammation.

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