A new strategy for enzyme replacement therapy

Significance 

Soluble guanylyl cyclase is the major cellular receptor for the intercellular messenger nitric oxide (NO) and mediates a wide range of physiological effects through elevation of intracellular cGMP levels. Indeed, many diseases are believed to be caused by defects in signaling pathways of body cells. In the future, bioactive nanocapsules could become a valuable tool for medicine to control these pathways. Researchers from the University of Basel have taken an important step in this direction: They succeed in having several different nanocapsules work in tandem to amplify a natural signaling cascade and influence cell behavior. The research team led by Professor Cornelia Palivan developed bioactive materials that could be suitable for this purpose. To achieve this, the researchers  combine nanomaterials with natural molecules and cells. The new research which is published in the journal ACS Nano demonstrated how enzyme loaded nano-capsules can enter cells and be integrated into their native signaling processes. By functionally coupling several nano-capsules, they are able to amplify a natural signaling pathway. In order to protect the enzymes from degradation in a cellular environment the research team loaded them into polymeric small capsules. Molecules can enter the compartment through biological pores specifically inserted in its synthetic wall and react with the enzymes inside.

The researchers conducted experiments with nanocapsules harboring different enzymes that worked in tandem: the product of the first enzymatic reaction entered a second capsule and started the second reaction inside. These nanocapsuled could stay operative for days and actively participated in natural reactions in mammalian cells.

One of the many signals that cells receive and process is nitric oxide (NO). It is a well-studied cellular mechanism since defects in the NO signaling pathway are involved in the emergence of cardiovascular diseases, but also in muscular and retinal dystrophies. The pathway encompasses the production of NO by an enzyme family called nitric oxide synthases (NOS). The NO can then diffuse to other cells where it is sensed by another enzyme named soluble guanylate cyclase. The activation of soluble guanylate cyclase starts a cascade reaction, regulating a plethora of different processes such as smooth muscle relaxation and the processing of light by sensory cells, among others. The authors produced capsules harboring NOS and soluble guanylate cyclase, which are naturally present in cells, but at much lower concentrations: the NOS-capsules, producing NO, act similarly to loudspeakers, ‘shouting’ their signal loud and clear; the soluble guanylate cyclase-capsules, act as ‘ears,’ sensing and processing the signal to amplify the response.

Using the intracellular concentration of calcium, which depends on the action of soluble guanylate cyclase, as an indicator, the scientists showed that the combination of both NOS and soluble guanylate cyclase loaded capsules makes the cells much more reactive, with an 8-fold increase in the intracellular calcium level. The study is an important step in the field of enzyme replacement therapy for diseases where biochemical pathways malfunction, such as cardiovascular diseases or several dystrophies

A new strategy for enzyme replacement therapy - Medicine Innovates
Figure legend: Enzyme-loaded nano-capsules work in tandem. The calcium level in the cells (green fluorescence) serves as an indicator that the system is working. Credit: University of Basel, Department of Chemistry

About the author

Cornelia G. Palivan  moved to the Department of Chemistry at the University of Basel where she was involved in projects using Electron Paramagnetic Resonance to characterize paramagnetic centers in free radicals, metal complexes, and proteins. The introduction to pulse EPR methods was made during her research stage with Professor Arthur Schweiger at the ETH Zurich (2003-2004). She returned to Basel in 2004, as Senior Group Leader in the group of Prof. Wolfgang Meier, and started to develop new hybrid materials at the nanoscale by combining self-assembling copolymers with compounds possessing biological activity, such as enzymes and enzyme-mimics.

Currently Cornelia is Professor in Physical Chemistry of the University of Basel, and the expertise of her group lies in particular in the design of bio-synthetic hybrid systems (nanoreactors, processors, electron-transfer nanodevices, and metal-exposed polymer membranes). Cornelia was awarded a number of fellowships during her career: Royal Society fellowship, EC-COST research fellowship, and TEMPUS mobility fellowship, supporting her collaboration with Dr. Bernard Goodman, at the Scottish Crop Research Institute, UK (1992, 1993, and 1998). In 1999 she was Academic guest at the Department of Physical Chemistry, University of Geneva. In addition to research which is run jointly with Professor Wolfgang Meier, Cornelia is scientific reviewer for Elsevier, Wiley, and ACS publications, and is involved in organizing the Swiss Soft Days workshops (since 2010).

Reference

Andrea Belluati, Ioana Craciun,Cornelia G. Palivan. Bioactive Catalytic Nanocompartments Integrated into Cell Physiology and Their Amplification of a Native Signaling Cascade. ACS Nano (2020). DOI: 10.1021/acsnano.0c05574

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