Nanoparticles hold great potential for biomedicine as they often outperform molecular agents in vitro. In vivo, though, most of the promising nanoagents become therapeutically inefficient because of rapid elimination from the bloodstream by the mononuclear phagocyte system (MPS).

Our team has been long involved in the development of drug delivery vehicles for the next-generation theranostics. For example, we develop smart¹ and biocomputing nanoagents² that can identify their targets via analysis of multiple molecular cues to provide better specificity. Like with many other advanced materials, it is hardly possible to prolong their blood circulation using a “stealth” coating approach (e.g., via surface PEGylation) without hampering their performance.

Being a bit frustrated about materials science solutions of the problem, we came up with a conceptually novel biotechnological approach. In our recent Nature Biomedical Engineering paper³ we report a universal method of dramatic improvement of nanoparticle circulation in blood without any need of their modification.

The principle is based on the natural function of macrophages to eliminate from the bloodstream the senescent and damaged blood cells. We hypothesized that forcing the MPS to intensify clearance of self blood cells (e.g., erythrocytes) might competitively suppress nanoparticle clearance. By administering allogeneic anti-erythrocyte antibodies we achieved a phenomenal increase (more than 30-fold) of nanoparticle circulation half-life. Our method of “MPS-cytoblockade” prolongs the blood circulation of nanoagents of virtually any composition and structure, ranging from 8-nm quantum dots to stealth FDA-approved liposomes, and micron-sized beads.

To illustrate the wide range of potential biomedical applications of the MPS-cytoblockade, we have shown remarkable enhancement of nanoparticle performance in three different applications:

• “Active” (antibody-mediated) targeting of blood cells,
• Magnetically-guided targeting of nanoagents to tumors (see Fig.2),
• Suppressing tumor growth and life-span extension in murine cancer model.

Importantly, anti-erythrocyte antibodies were long ago approved for administration to humans. They are widely used throughout the world for treatment of immune thrombocytopenia and rhesus-syndrome. This fact imparts cautious optimism for the translation of our cytoblockade technology to clinical trials.

We should note that the remarkable amount of in vivo measurements of nanoparticle circulation kinetics in this study would be hardly possible without our registration technique of magnetic particle quantification (MPQ)⁴. The method is based on non-linear magnetization of particles by a two-frequency magnetic field and recording the inductive response at a combinatorial frequency. In the study, an MPQ detector non-invasively recorded the genuine kinetics in the tail blood flow of each individual rodent at a 3-s temporal resolution (see example in Fig. 1). This way, the data were devoid of artefacts and errors inherent to the techniques based on blood sampling. Thereby, MPQ yielded more detailed data with considerably fewer laboratory animals, adhering to the 3R ethical principle (Replacement, Reduction and Refinement).

We believe that the proposed technology may open doors for in vivo use of the most advanced nanoagents with the primary focus on functionality rather than the stealth characteristics. Nanorobots and other novel nanoprobes, actuators, and nanovehicles according to the bravest ideas offered by materials science may be instantaneously introduced into life science research in vivo and then rapidly perfected for clinical use.

References

1. Cherkasov, V. R., et al. Nanoparticle beacons: Supersensitive smart materials with on/off-switchable affinity to biomedical targets. ACS nano, 14, 1792-1803 (2020).
2. Nikitin, M. P., et al. Biocomputing based on particle disassembly. Nature nanotechnology, 9, 716-722 (2014).
3. Nikitin, M.P., et al. Enhancement of the blood-circulation time and performance of nanomedicines via the forced clearance of erythrocytes. Nature Biomedical Engineering (2020).
4. Nikitin, M.P., et al. Ultrasensitive detection enabled by nonlinear magnetization of nanomagnetic labels. Nanoscale, 10, 11642-11650 (2018).