| Summary: |
The development of efficient therapeutics for viral diseases stands currently among the biggest scientific challenges in global health. The serious societal
problems caused by the recent pandemic originated by the SARSCov-2 virus are a stark reminder of this pressing and continuous need. Among key strategies to
fight viruses is the development of smart nanocarriers that efficiently transport therapeutic RNA into cells to activate the immune system. RNA-based treatments
hold the promise of achieving de novo/increased expression of specific therapeutic proteins (exogenous mRNA), like viral antigens, or silencing of pathological
genes (with small interfering RNA, siRNA). The bottom-up design, at molecular level, of efficient nanocarriers using the concepts and experimental tools of
surface and colloid chemistry is key to a successful strategy, but it is also a challenging endeavor due to some critical obstacles to overcome. A successful RNA
delivery system should encapsulate RNA efficiently, protect it from degradation, deliver it to cells and facilitate its endosomal escape for gene expression or gene
silencing. The nanovector efficiency depends on the formulation constituents, nanocarriers' physicochemical features and interfacial behavior with the tissues
and cells. Amphiphile-based nanocarriers (i.e. surfactants and/or lipids) have been extensively validated for RNA delivery, for their loading efficiency but
importantly for their generally favorable safety profile, and several are already available in the clinic, including as antiviral vaccines. Nonetheless, there is still
need for improvement specially regarding stability, safety, efficacy and, inevitably, cost.
The aim of this project is to develop versatile and stimuli-responsive (hence, smart) surfactant-based nanocarriers for RNA anti-viral therapeutics. Our approach
is based on a coherent and multidisciplinary combination of organic synthesis, colloid chemistry and biological studies. The  |
Summary
The development of efficient therapeutics for viral diseases stands currently among the biggest scientific challenges in global health. The serious societal
problems caused by the recent pandemic originated by the SARSCov-2 virus are a stark reminder of this pressing and continuous need. Among key strategies to
fight viruses is the development of smart nanocarriers that efficiently transport therapeutic RNA into cells to activate the immune system. RNA-based treatments
hold the promise of achieving de novo/increased expression of specific therapeutic proteins (exogenous mRNA), like viral antigens, or silencing of pathological
genes (with small interfering RNA, siRNA). The bottom-up design, at molecular level, of efficient nanocarriers using the concepts and experimental tools of
surface and colloid chemistry is key to a successful strategy, but it is also a challenging endeavor due to some critical obstacles to overcome. A successful RNA
delivery system should encapsulate RNA efficiently, protect it from degradation, deliver it to cells and facilitate its endosomal escape for gene expression or gene
silencing. The nanovector efficiency depends on the formulation constituents, nanocarriers' physicochemical features and interfacial behavior with the tissues
and cells. Amphiphile-based nanocarriers (i.e. surfactants and/or lipids) have been extensively validated for RNA delivery, for their loading efficiency but
importantly for their generally favorable safety profile, and several are already available in the clinic, including as antiviral vaccines. Nonetheless, there is still
need for improvement specially regarding stability, safety, efficacy and, inevitably, cost.
The aim of this project is to develop versatile and stimuli-responsive (hence, smart) surfactant-based nanocarriers for RNA anti-viral therapeutics. Our approach
is based on a coherent and multidisciplinary combination of organic synthesis, colloid chemistry and biological studies. The surfactants are novel and bioinspired, derivatized from amino acids, and possess a gemini structure, which allows for structural versatility. Gemini surfactants contain two polar headgroups
linked by a covalent spacer, and their aggregation properties depend inter alia on the spacer length. Cationic surfactants are typically used in nucleic acid
delivery (electrostatic-driven complexation), together with helper lipids, whose basic role is to facilitate cell entry and/or decrease possible surfactant
cytotoxicity. In our project, (i) the charge state of the gemini surfactants is pH-dependent (can be neutral or cationic, with +2 or +4 valence), due to presence of
ionizable amine groups in their polar headgroup, and (ii) they also have cleavable chemical bonds, ester and/or disulfide bonds, both labile and dependent on
local pH, redox environment and enzymatic activity. The rationale is that these molecular features will allow the surfactant-based RNA nanocarriers to change
sequentially their properties (namely charge and chemical stability) along the delivery path to be effective in the different critical steps: initial RNA
complexation/encapsulation; nanovector stability in the systemic circulation; cell internalization; and endosomal escape leading to RNA expression.
The project involves a team of organic chemists, colloid chemists and biologists, who have previously worked together in the design and test of drug and gene
delivery systems. We build on previous work to propose novel and innovative systems for RNA delivery. Seven tasks are envisaged. Tasks 1-2 involve the
synthesis of three fami |