Josep Mas Roselló

Unsaturated amino lipids were synthesized to study the role of unsaturation in lipid nanoparticle (LNP)‐mediated mRNA delivery. A lipid series with a Citronellol tail (4A3‐Cit) was identified from a library screen. Employing 4A3‐Cit in new Selective ORgan Targeting (SORT) formulation resulted in an 18‐fold increase in mRNA expression over saturated LNPs. The findings provide insights into how unsaturation and SORT mixing can promote mRNA delivery.

Abstract

Lipid nanoparticles (LNPs) represent the leading concept for mRNA delivery. Unsaturated lipids play important roles in nature with potential for mRNA therapeutics, but are difficult to access through chemical synthesis. To systematically study the role of unsaturation, modular reactions were utilized to access a library of 91 amino lipids, enabled by the synthesis of unsaturated thiols. An ionizable lipid series (4A3) emerged from in vitro and in vivo screening, where the 4A3 core with a citronellol‐based (Cit) periphery emerged as best. We studied the interaction between LNPs and a model endosomal membrane where 4A3‐Cit demonstrated superior lipid fusion over saturated lipids, suggesting its unsaturated tail promotes endosomal escape. Furthermore, 4A3‐Cit significantly improved mRNA delivery efficacy in vivo through Selective ORgan Targeting (SORT), resulting in 18‐fold increased protein expression over parent LNPs. These findings provide insight into how lipid unsaturation promotes mRNA delivery and demonstrate how lipid mixing can enhance efficacy.

A multifunctional graphene conjugate was designed for cancer treatment, as reported by E. Miyako, A. Bianco et al. in their Communication (DOI: https://doi.org/10.1002/anie.20191611210.1002/anie.201916112). The image depicts the three regalia—crown, orb, and sword—representing triple chemically modified graphene as the strongest approach for cancer therapy.

Mighty T‐rex: Phototriggered topology‐reset execution (T‐rex) on cyclic poly(dimethylsiloxane)s (PDMSs) functionalized in‐chain with hexaarylbiimidazole moieties enabled the formation of cyclic PDMSs with a desired mixing state of ring sizes, depending on the UV‐irradiation conditions (see picture). T‐rex enabled repeatable and dramatic changes in the rheological properties of PDMS while maintaining its liquid state.

Abstract

Repeatable topological transformation of polymers for the modulation of material functions is a challenge. We have developed a method for repeatedly resetting a cyclic macromolecular architecture to a linear architecture by photostimulation, namely, topology‐reset execution (T‐rex) based on the photochemistry of hexaarylbiimidazoles (HABIs). We synthesized cyclic poly(dimethylsiloxane)s (PDMSs) of various ring sizes with HABIs linked in the chains. UV irradiation of the cyclic PDMSs produced telechelic linear PDMSs with triphenylimidazolyl radical (TPIR) end groups. After termination of UV irradiation, end‐to‐end recyclization occurred by the recoupling of TPIRs. The cyclic PDMSs also responded to ultrasound, which decreased their molecular weight (MW) by site‐specific cleavage of in‐chain HABI moieties, and we are able to reset the MWs by subsequent phototriggered T‐rex. Furthermore, T‐rex enabled solvent‐free switching of the rheological properties of the materials while retaining the liquid character of PDMS.

Special agents on the job: Supramolecular curcumin nanoagents were fabricated by amino acid coordination driven self‐assembly (see picture). The biological stability of curcumin was significantly improved through both coordination and molecular stacking in the nanoagents, the size of which could be readily manipulated. These favorable therapeutic features substantially enhanced the antitumor activity of curcumin without discernible side effects.

Abstract

Clinical translation of curcumin has been highly obstructed by the rapid degradation and poor tissue absorption of this agent. Herein, we report on the generation of supramolecular curcumin nanoagents through amino acid coordination driven self‐assembly to simultaneously increase the biological stability and tumor accumulation of curcumin. The biological stability of curcumin was significantly improved both through coordination and through molecular stacking. The sizes of these nanoagents can be readily manipulated to facilitate tumor accumulation. These favorable therapeutic features, together with high drug‐loading capacities and responses to pH and redox stimuli, substantially enhanced the antitumor activity of curcumin without discernible side effects. Hence, supramolecular curcumin nanoagents may hold promise in moving forward the clinical application of curcumin as an effective anticancer drug.

Putting a number on it: An equation is derived based on Pauling's equation and is shown to accurately estimate the bond enthalpies of small molecular fragments to transition‐metal surfaces.

Abstract

Understanding what controls the strength of bonding of adsorbed intermediates to transition‐metal surfaces is of central importance in many technologies, especially catalysis and electrocatalysis. Our recently measured bond enthalpies of −OH, −OCH₃, −O(O)CH and −CH₃ to Pt(111) and Ni(111) surfaces are fit well (standard deviation of 7.2 kJ mol⁻¹) by a predictive equation involving only known parameters (gas‐phase ligand–hydrogen bond enthalpies, bond enthalpies of adsorbed H atoms to that surface, electronegativities of the elements, and group electronegativities of the ligands). This equation is based upon Pauling's equation, with improvements introduced by Matcha, derived here following manipulations of Matcha's equation similar to (but going beyond) those introduced by Schock and Marks to explain ligand–metal bond enthalpy trends in organometallic complexes.

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