A long-term and huge challenge in nanomedicine is the substantial uptake and rapid clearance mediated by the mononuclear phagocyte system (MPS), which enormously hinders the development of nanodrugs. Inspired by the natural merits of extracellular vesicles, we therefore developed a combined "eat me/don't eat me" strategy in an effort to achieve MPS escape and efficient drug delivery. Methodologically, cationized mannan-modified extracellular vesicles derived from DC2.4 cells were administered to saturate the MPS (eat me strategy). Then, nanocarriers fused to CD47-enriched exosomes originated from human serum were administered to evade phagocytosis by MPS (don't eat me strategy). The nanocarriers were also loaded with antitumor drugs and functionalized with a novel homing peptide to promote the tumour tissue accumulation and cancer cell uptake (eat me strategy). The concept was proven in vitro as evidenced by the reduced endocytosis of macrophages and enhanced uptake by tumour cells, whereas prolonged circulation time and increased tumour accumulation were demonstrated in vivo. Specially, the strategy induced a 123.53% increase in tumour distribution compared to conventional nanocarrier. The study both shed light on the challenge overcoming of phagocytic evasion and provided a strategy for significantly improving therapeutic outcomes, potentially permitting active drug delivery via targeted nanomedicines.

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Overcoming the epithelial barriers to enhance drug transport is a focused topic for gastrointestinal, intratracheal, intranasal, vaginal, and intrauterine delivery. Nanomedicines with targeting functionization promote such a process owing to specific ligand–receptor interaction. However, compared to the cell uptake of targeting nanotherapies, currently few studies concentrate on their transcytosis including endocytosis for “in” and exocytosis for “out”. In fact, the cellular regulatory mechanism for these pathways as well as the principle of ligand’s effect on the transcytosis are almost ignored. Here, we fabricated transferrin (Tf) functionalized nanogranules (Tf-NG) as the nanomedicine model and confirmed the difference in polar distributions of Tf receptors (TfRs) between two epithelium models (bipolarity for Caco-2 and unipolarity for MDCK cells). Compared to the nonspecific reference, Tf-conjugation boosted the endocytosis by different pathways in two cell models and transformed the intracellular route of Tf-NG in both cells differently, affecting exocytosis, recycling, and degradation but not the secretion pathway. Only bipolar cells could establish a complete transport flow from “in” to “out”, leading to the enhanced transcytosis of Tf-NG. Importantly, epithelia could make responses to Tf-NG transcytosis. Based on the quantitative proteomics, the intracellular trafficking of Tf-NG altered the protein expression profiles, in which the endocytosis- and transcytosis-related proteins were specifically upregulated. Particularly, only bipolar cells could positively feed back to such trafficking via accelerating the subsequent Tf-NG transcytosis. Here, all the cell transport of Tf-NG was polarity associated. In summary, Tf modification elevated the transcytosis of Tf-NG across the epithelium by triggering the polarity-associated transport flow and positive cell feedback loop. These findings provided an insight into the targeting nanodelivery for efficient transport through epithelial barriers.

Oral administration is an ideal alternative for drug delivery due to its convenience and safety. However, oral protein delivery is limited by biological barriers such as the mucus barrier and epithelial barrier, which hamper drugs from entering the blood successfully. Here we presented PC6/CS NPs, a thiolated-polymerbased nanodrug delivery system in the form of poly(acrylic acid)− cysteine−6-mercaptonicotinic acid (PAA−Cys−6MNA, PC6), which is a kind of preactivated thiolated polymer, coated on chitosan (CS) nanoparticles (NPs). Its ability to overcome the mucus barrier and epithelial barrier was investigated. The existence of PC6 made the NPs prone to penetrate the mucus layer as well as strengthened the transcellular transport of insulin on epithelial cells. PC6/CS NPs efficiently enhanced the oral bioavailability of insulin to 16.2%. The improvement resulted from the function of PC6: (1) "diluting" mucus to promote nanoparticle penetration, (2) opening a tight junction to help insulin transport via the paracellular pathway, (3) making the nanoparticle more electrically neutral during the penetration process, and (4) uncoating from PC6/CS NPs so that positive CS NPs were adhered and uptaken by epithelial cells. Our study proves that PC6/CS NPs, which can achieve mucus penetration and epithelial permeation efficiently, are a potential nanocarrier for oral protein delivery.