The Evasive Agents: How Drug-delivering Nanoparticles Avoid the Immune System

The Evasive Agents: How Drug-delivering Nanoparticles Avoid the Immune System

By Siwei Zhang

The use of artificially-designed and synthesized nanoparticles as drug delivery vehicles into the human body via bloodstream infusion or direct injection has been widely applied in recent years. However, there is one important factor that severely restricted the application of such nanoparticle drug delivery mechanism: the immune system and the accompanied immune responses. The drug-delivering nanoparticles, whose surface epitopes are drastically different from endogenous proteins if not modified or clocked, routinely suffer extensive attacks from the immune system and get consumed by immune-responsive cells, especially macrophages. To compensate the loss of particles due to such particle-depleting effects, sometimes very high doses of particles need to be administered to patients who frequently elicit massive autoimmune responses including high fever, spiked white blood cell count, and even asphyxia. Moreover, in several cases, such nanoparticles are successfully presented as antigens and the immune system generates corresponding antibodies which neutralize any subsequent input of the same nanoparticles to render the treatment efforts void.

Several successful attempts have been exploited to disguise the drug-delivering nanoparticles and to make them evasive to the body’s immune system. One early investigation uses virus-like nanoparticles with self-assembling ability in vivo. In such cases, the particles carrying toxins against tumors are administered as monomers, and the nanoparticles only become effective once finished their self-assembling process. Due to the specially-designed arrangement of surface peptide sequences that resemble a known protein that specifically resides on the cell membranes of tumor cells, this peptide coating not only allows efficient evasion against immune responses but it is also highly specific to tumor cells with poor specificity and high cytotoxicity.

In another investigation, researchers applied a peptide coating, derived from the CD47 protein, onto the surface of drug-carrying nanoparticles. Because of the presence of CD47 fragments on the surface of the nanoparticles, macrophages specifically recognize no particles and consider them being safe. More encouragingly, these nanoparticles have been further conjugated with paclitaxel, a widely-used and highly-potent tumor-suppressing molecule. Although this type of nanoparticle lacks tumor-specific binding sites or recognition sequences, it was nevertheless found to be highly accumulated in the tumor tissue for their haphazard structure and leaky blood vessels.

A most recent research in UC San Diego again used such coating strategy to make the nanoparticles evasive to the immune system. Whilst the previous investigation used fragments of CD47 protein as a marker to disguise nanoparticles, this current investigation applied membranes from human platelets – the factor that plays an important role during blood coagulation – to coat the nanoparticles used. This naturally-derived membrane provides a more comprehensive set of human endogenous proteins that can be presented on the surface of nanoparticles, thus further reducing the potential of macrophage detection and subsequent immune responses. An example of its application has been reported to conjugate such coated nanoparticles with docetaxel, a chemical that used to prevent excessive thickening of damaged artery walls after surgery. Since platelets have a natural tendency to accumulate on the surface of damaged blood vessels, this nanoparticle delivery mechanism makes the docetaxel treatment to be more efficient than direct administration of docetaxel without delivery vehicles.

To sum up, with the current development of advanced nanotechnology, it is highly attractive to infuse modern immunology techniques into nanoparticle research to give a boost to site-specific and efficient drug delivery in vivo. Whilst such hybridization of synthetic and biological factors may not be as easy as promised, it is surely a forerunning technology with a high reward potential worth investment.


Minimal “Self” peptides that inhibit phagocytic clearance and enhance delivery of nanoparticles. Science. 2013 Feb 22; 339 (6122): 971-5. Rodriguez PL1, Harada T, Christian DA, Pantano DA, Tsai RK, Discher DE.

Nanoparticle biointerfacing by platelet membrane cloaking. Nature (2015) doi: 10.1038/nature15373, Che-Ming J Hu et al.

Structural plasticity of a transmembrane peptide allows self-assembly into biologically active nanoparticles. PNAS 2011 Jun 14; 108 (24): 9798-803. Tarasov SG1, Gaponenko V, Howard OM, Chen Y, Oppenheim JJ, Dyba MA, Subramaniam S, Lee Y, Michejda C, Tarasova NI.

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