Editors' ChoiceAutoimmunity

Nanomedicine goes to school

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Science Translational Medicine  24 May 2017:
Vol. 9, Issue 391, eaan4291
DOI: 10.1126/scitranslmed.aan4291

Abstract

Integration of engineering and immunological tools proposes design guidelines for nanoparticles that direct T cells toward specific phenotypes to control autoimmune disease.

With summer approaching, the days are getting longer and vacations are becoming real, but for many budding scientists and engineers, final exams stand in the way of this escape. Final exams—and problem-solving more generally—are easier to tackle if underlying principles can be assembled into complex ideas, as opposed to trial-and-error, or memorization. This same challenge faces translational medicine. The cost, complexity, and safety concerns of preclinical research and human trials promote empirical approaches that, although useful, are inefficient and hindered by missing fundamental insight.

Singha and Shao and colleagues have integrated engineering and immunology to elucidate the specific features of nanoparticles useful in generating selective immunological tolerance. This selectivity is in contrast to broad suppression of existing autoimmune therapies. In past work, self-molecules attacked during autoimmunity were displayed on these particles in protein complexes recognized by self-reactive T cells, driving expansion and polarization toward protective regulatory T cells (Tregs). Here, by systemically altering the chemistry, binding capacity, and spacing of peptide-protein complexes on nanoparticles, optimal valencies and molecular spacings were identified for T cell recognition and Treg expansion. Intriguingly, mathematical affinity models and transgenic T cell studies revealed that the dose of peptide-protein complexes controls the magnitude of T cell expansion, whereas the density of complexes on nanoparticles governs polarization toward Treg. Transmission electron and super-resolution microscopy revealed in mouse and human T cells that these effects result from sustained clustering of T cell receptors caused by nanoparticles displaying cognate peptide-protein complexes above a threshold level. This clustering up-regulates transcripts for an important tolerogenic phenotype, type 1 Tregs.

Since nanomedicines are increasing in complexity and often contain synthetic components, simplicity and biocompatibility are important considerations. Several recent nanomedicines targeting autoimmunity do not rely on recombinant proteins as above; yet, this new report provides strong evidence of safety in zebrafish embryos—an important vertebrate model—and in mouse biochemistry and biodistribution studies. Balancing this equation of efficacy, safety, and simplicity is an important assignment to push new therapies forward. The work summarized here provides exciting insight that will help nanomedicines make the grade by linking specific design features to distinct immunological outcomes.

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