© 2019 The Royal Society of Chemistry. We have developed and tested copper oxide nanoparticles (CuONPs) grafted with (3-glycidyloxypropyl)trimethoxysilane (GLYMO) and coupled with 4-hydroxyphenylboronic acid (4-HPBA), which provides a very strong boost of their action as anti-algal and anti-yeast agents. The boronic acid terminal groups on the surface of the CuONPs/GLYMO/4-HPBA can form reversible covalent bonds with the diol groups of glycoproteins and carbohydrates expressed on the cell surface where they bind and accumulate, which is not based on electrostatic adhesion. Results showed that, the impact of the 4-HPBA grafted CuONPs on microalgae (C. reinhardtii) and yeast (S. cerevisiae) is several hundred percent higher than that of bare CuONPs and CuONPs/GLYMO at the same particle concentration. SEM and TEM imaging revealed that 4-HPBA-functionalized CuONPs nanoparticles can accumulate more on the cell walls than non-functionalized CuONPs. We found a marked increase of the 4-HPBA functionalized CuONPs action on these microorganisms at shorter incubation times compared with the bare CuONPs at the same conditions. We also showed that the anti-algal action of CuONPs/GLYMO/4-HPBA can be controlled by the concentration of glucose in the media and that the effect is reversible as glucose competes with the diol residues on the algal cell walls for the HPBA groups on the CuONPs. Our experiments with human cell lines incubated with CuONPs/GLYMO/4-HPBA indicated a lack of measurable loss of cell viability at particle concentrations which are effective as anti-algal agents. CuONPs/GLYMO/4-HPBA can be used to drastically reduce the overall CuO concentration in anti-algal and anti-yeast formulations while strongly increasing their efficiency.