A combined “eat me/don't eat me” strategy based on extracellular vesicles for anticancer nanomedicine

Abstract

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.

Camouflage strategies for therapeutic exosomes evasion from phagocytosis

“…Corroborating the previous findings with the research work recently carried out by Yang et al [11] and Belhadj et al [66] , it was also shown that the expression of the CD47 protein on the surface of exosomes endows them with the ability to evade phagocytosis and consequently to increase their circulating half-life. Yang et al [11] reported that CD47 overexpression in exosomes extended the half-life by 3-fold in the bloodstream, with no obvious in vivo toxicity or immunogenicity in mice at the different dosages and time points tested.…”

“…Yang et al [11] reported that CD47 overexpression in exosomes extended the half-life by 3-fold in the bloodstream, with no obvious in vivo toxicity or immunogenicity in mice at the different dosages and time points tested. Likewise, Belhadj et al [66] observed that the incorporation of CD47 in the surface membrane of exosomes reduce the endocytosis by macrophages, enhancing the uptake by the target tumor cells, prolonging the in vivo circulation time, lowering the distribution to the liver and spleen, and increasing tumor accumulation.…”

The exosome journey: from biogenesis to uptake and intracellular signalling

“…Equally, the presence of certain receptors facilitates evasion from the host immune system. For instance, CD47 at the surface of engineered exosomes contributes to evasion from host immune cells during circulation in vivo [ 109 ]. Complex lipids also influence exosome targeting as observed in cancer cells.…”

Targeted delivery of extracellular vesicles in heart injury

“…In the therapeutic anticancer area, Belhadj et al . 160 exploited a combined “eat me/don't eat me” tactic to reduce endocytosis of macrophages. For the “eat me” component, EVs extracted from DC2.4 cells were modified with cationic mannan to saturate the MPS.…”