Boronate-affinity controllable-oriented surface imprinting (BACOSI), codified in a 2017 Nature Protocols paper by Xing, Wang, Bie, He and Liu, prepares antibody-mimicking molecularly imprinted polymers (MIPs) for glycoproteins, glycans and monosaccharides by immobilizing a cis-diol-bearing template on a boronic-acid-functionalized substrate and growing a biocompatible, self-polymerized imprinting layer (dopamine/3-aminophenylboronic acid co-polymerization or tetraethyl orthosilicate silica condensation) whose thickness is tuned by the imprinting time. The protocol itself acknowledges that the method's generality is bounded by unresolved development needs: the free-cis-diol template requirement (which excludes, for example, many glycosaminoglycans), the small set of monomers verified to give controllable uniform layers, unreliable oriented immobilization of glycopeptides with long peptide chains, class-level cis-diol recognition that falls short of lectin-like specificity, and unexplored limits of applicability including long-term reuse. Every strand shows substantive partial progress - polyphenol monomer platforms, anion-exchange and lectin-mediated oriented imprinting of cis-diol-free templates, semi-template and glycopeptide-epitope strategies, boroxole-based synthetic lectins - but no strand is resolved: 2026 reviews still name broadening the oriented-immobilization repertoire and the monomer palette as persistent objectives. The problem of generalizing BACOSI into a controllable, broadly applicable synthetic-antibody platform remains open.

Background

Molecularly imprinted polymers (MIPs) are synthetic receptor materials made by polymerizing monomers around a template molecule and then removing the template, leaving cavities that rebind the template and its close analogues; they are pursued as antibody mimics for sensing, separation and diagnosis because they are cheap, stable and storable, yet many imprinting approaches are poorly controllable and narrow in template scope. Boronate affinity is the reversible covalent interaction between a boronic acid and a cis-diol (two adjacent hydroxyls on the same side of the molecular framework): above the boronic acid's pKa a cyclic boronate ester forms, and it dissociates again at mildly acidic pH, giving gentle, switchable binding. Glycoproteins - proteins carrying covalently attached glycans (oligosaccharide chains) - plus free glycans, glycopeptides (glycan-bearing peptide fragments) and monosaccharides all expose cis-diol groups in their sugar residues, so boronic-acid-functionalized surfaces capture them as a class. Glycosaminoglycans (GAGs), by contrast, are linear sulfated polysaccharides (heparin, chondroitin sulfate and related molecules) in which many sugar units are N-substituted, epimerized or O-sulfated, so a large fraction lack free cis-diols and escape boronate capture. Lectins are natural glycan-binding proteins that recognize specific glycan structures; reproducing such fine specificity synthetically is a standing goal because boronate affinity alone binds essentially any cis-diol-containing molecule. Building on their earlier glycan-oriented surface imprinting work (Bie et al., 2015), the Nanjing University group of Zhen Liu developed boronate-affinity controllable-oriented surface imprinting: a template (glycoprotein, glycopeptide, glycan or monosaccharide) is first immobilized in an oriented fashion on a boronic-acid-functionalized substrate through boronate affinity; a biocompatible, self-polymerizing monomer system - dopamine/3-aminophenylboronic acid (APBA) co-polymerization or tetraethyl orthosilicate (TEOS) sol-gel condensation, with aniline and aniline/2-anilinoethanol also reported - then grows an imprinting layer whose thickness is set simply by the polymerization time (recommended layer thickness is about one-third to two-thirds of the template's molecular size); mild acid removes the template and frees the oriented cavities. The 2017 Nature Protocols paper (Xing et al.) standardized this protocol and demonstrated MIPs with antibody-like binding toward glycoproteins (for example transferrin and ovalbumin), glycans and monosaccharides, applicable to affinity separation, disease diagnosis and bioimaging. Performance in this field is conventionally quantified by binding constants, adsorption capacity, and the imprinting factor - the ratio of binding by the imprinted polymer to that of a non-imprinted control prepared identically without template. The protocol's own limitations section, however, states that the approach requires templates bearing free cis-diols (leaving many GAGs and other cis-diol-free targets inaccessible), that the set of biocompatible self-polymerizable monomers verified to yield controllable, uniform imprinting layers is limited, that glycopeptides with long peptide chains cannot be immobilized in a reliably oriented manner because their three-dimensional conformations are hard to predict, that boronate affinity confers only class-level cis-diol recognition and may not reproduce lectin-like specificities, and that the limits of applicability (extreme templates, highly porous substrates, long-term stability under repeated reuse, throughput and large-scale manufacturing) remain to be systematically explored. A companion account by the same group (Liu and He, 2017) frames the same agenda as moving boronate-affinity materials 'from class selectivity to biomimetic specificity'.

Problem Statement

How can boronate-affinity controllable-oriented surface imprinting be generalized from its demonstrated scope - cis-diol-bearing templates (glycoproteins, short glycopeptides, glycans, monosaccharides) imprinted with a handful of self-polymerizable monomers - into a broadly applicable, controllable synthetic-antibody platform? As acknowledged in the source protocol's limitations and the group's companion accounts, the following independent open development directions all constrain the same three-step method (oriented template immobilization, controllable self-polymerized layer growth, mild template removal): (1) Monomer repertoire - identify or design biocompatible, self-polymerizable monomers or chemical modifications, beyond dopamine/3-aminophenylboronic acid co-polymerization, TEOS silica condensation and aniline/2-anilinoethanol, that simultaneously provide broad chemical functionality, precise time-controlled growth of uniform nanometre-scale imprinting layers in aqueous media, and compatibility with oriented boronate immobilization. (2) Template scope - extend controllable-oriented surface imprinting to targets that lack free cis-diols, such as many glycosaminoglycans, whether through alternative reversible oriented-immobilization chemistries or template-anchoring-free imprinting modes, while retaining mild elution and oriented cavity formation. (3) Flexible templates - make oriented immobilization reliable for glycopeptides with long peptide chains whose three-dimensional conformations cannot be predicted, going beyond ad hoc workarounds such as enzymatic trimming to short glycopeptides or use of intact glycoproteins as semi-templates. (4) Selectivity - refine recognition beyond class-level cis-diol binding toward lectin-like specificity (discrimination of glycan linkage, stereochemistry and glycoform) through monomer design or hybrid strategies. (5) Robustness and limits - establish the applicability boundaries of the platform (extreme templates, highly porous substrates where surface-area-versus-control trade-offs arise, long-term stability under repeated reuse in complex matrices) and the throughput and scale-up conditions under which controllability is retained. These five directions are independent open research targets rather than a conjunctive checklist: each can be advanced on its own, and none is a precondition for the others.

References

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