Joost N. H. Reek

The range of metalation states within porphyrins provide a facile approach to tunable optical, electrochemical and catalytic properties. Spatial organization of metalloporphyrin units can yield additional emergent properties, with precise organization in Pd ₁₂ L ₂₄ (L = Ligand) supramolecular nanosphere systems made possible by metal‐mediated self‐assembly. Here, we explore synthetic approaches to form porphyrin‐appended Pd ₁₂ L ₂₄ nanospheres, featuring porphyrins with different metal centers. New synthetic strategies are devised and explored en route to porphyrin‐equipped nanosphere building blocks. We determine that Pd ²⁺ , Cu ²⁺ , Fe ³⁺ , and Zn ²⁺ metalated porphyrins can withstand the nanosphere formation process, while Mg ²⁺ porphyrins experience transmetalation under nanosphere formation conditions. The free base porphyrins are easily metalated by the metal precursor [Pd(MeCN) ₄ ](BF ₄ ) ₂ , required for Pd ₁₂ L ₂₄ nanosphere formation, but free base porphyrin‐containing nanospheres are readily formed under kinetic control when the precise stoichiometry is employed. With these newly developed synthetic methods, porphyrin‐equipped building block compounds can form Pd ₁₂ L ₂₄ nanosphere assemblies with porphyrins placed at both the exohedral and endohedral sites of the supramolecular construct. The cage‐appended porphyrins retain metallation state dependent optical properties, although transient absorption measurements reveal much faster photophysics than molecular controls. Therefore, porphyrin‐containing supramolecular nanospheres can now be explored as energy transduction systems with potential applications in artificial photosynthesis.

Inorganic anticancer drugs such as cisplatin remain central to chemotherapy but are limited by poor tumor selectivity, rapid clearance, and off‐target toxicity. We recently developed cationic Pt ₂ L ₄ nanocages with 12‐fold higher anticancer activity than cisplatin in PC‐3M‐Pro4 cells in vitro, but their positive charge causes rapid extravasation and renal clearance in vivo. Here, we re‐engineer lipid nanoparticles (LNPs) into charge‐reversed lipid nanoparticles (revLNPs) capable of efficiently encapsulating cationic Pt ₂ L ₄ nanocages. Pt ₂ L ₄ ‐loaded revLNPs retain high cancer‐cell uptake and cytotoxicity in vitro comparable to the free drug. Following intravenous administration, they show prolonged circulation, reduced vessel‐wall leakage, and favorable biodistribution in zebrafish embryos. In mice, revLNPs exhibit a 1.7‐fold longer plasma half‐life than the clinically approved Onpattro LNP formulation while maintaining characteristic liver and spleen tropism. In zebrafish xenografts, a single injection induces substantial tumor regression, reaching 20% in PC‐3M‐Pro4 and 72% in MDA‐MB‐231 tumors, and outperforms Lipocisplatin despite a ten‐fold lower therapeutic dose. These results establish revLNPs as a broadly applicable delivery platform that overcomes solubility, biodistribution, and pharmacokinetic barriers of cationic inorganic drugs, enabling their effective use in vivo.

Temporal input dependence emerges from a chemical reaction network containing a carbodiimide driven equilibrium coupled to a photochemical decarboxylation.

Chemotherapy stands out as an effective cancer treatment, although typically accompanied by side effects arising from systemic toxicity of anticancer drugs due to the limited specific targeting of tumor cells. In this study, we present a self‐assembled Ru‐based polysaccharide photocatalyst that selectively targets cancer cells and catalyzes the prodrug‐to‐drug conversion upon exposure to visible light. The self‐assembled photocatalyst forms via supramolecular interactions between β‐cyclodextrins attached to the hyaluronic acid polymer and the adamantane‐functionalized tris(bipyridine)ruthenium(II) complex. This polymer supported photocatalysts enables precise targeting of cancer cells as it recognized the CD44 receptor, while the light driven conversion allows for temporal and spatial control over drug production. We demonstrate that both the pro‐probe (Rho‐N ₃ ) and the prodrug (DOX‐L‐N ₃ ) can be efficiently converted into the respective active compounds through visible light irradiation, using the supramolecular photocatalyst. The supramolecular photocatalyst targets MCF‐7 cancer cells over noncancerous NIH3T3 cells, converting Rho‐N ₃ upon irradiation only when the catalyst is present in the cell. In line with this, irradiation of MCF‐7 cells that were exposed to DOX‐L‐N ₃ induces increased cell death. This strategy is a way forward to efficient, controllable, and targeted activation of prodrugs within cancer cells.

Multi‐stimuli‐responsive assembly of water‐soluble, high‐nuclearity metal–organic cages (MOCs) offers attractive opportunities for adaptive supramolecular systems, but balancing structural definition with flexibility remains a central challenge. Here, we report that an adaptive ligand ( L2 ) enables access to a series of M _3n L _2n cages within a single coordination framework, including octahedral, tubular, and bowl‐shaped Pd ₆ ( L2 ) ₄ cages, as well as a Pd ₁₂ ( L2 ) ₈ icosahedron. These architectures reversibly interconvert in response to changes in temperature, concentration, solvent environment, and guest binding. In contrast, a rigid analogue ( L1 ) yields a single Pd ₆ ( L1 ) ₄ octahedral cage. Mechanistic studies, combined with single‐crystal X‐ray diffraction analysis, reveal that interconversion between cages of different nuclearities proceeds primarily via cage isomerization within intact frameworks rather than through classical stepwise growth, providing a kinetically efficient route to higher‐order structural complexity and organization. These results establish the integration of conformational adaptivity with cage isomerization pathways as a general design principle for multi‐stimuli‐responsive supramolecular systems in water.

Multi‐stimuli‐responsive assembly of water‐soluble, high‐nuclearity metal–organic cages (MOCs) offers attractive opportunities for adaptive supramolecular systems, but balancing structural definition with flexibility remains a central challenge. Here, we report that an adaptive ligand ( L2 ) enables access to a series of M _3n L _2n cages within a single coordination framework, including octahedral, tubular, and bowl‐shaped Pd ₆ ( L2 ) ₄ cages, as well as a Pd ₁₂ ( L2 ) ₈ icosahedron. These architectures reversibly interconvert in response to changes in temperature, concentration, solvent environment, and guest binding. In contrast, a rigid analogue ( L1 ) yields a single Pd ₆ ( L1 ) ₄ octahedral cage. Mechanistic studies, combined with single‐crystal X‐ray diffraction analysis, reveal that interconversion between cages of different nuclearities proceeds primarily via cage isomerization within intact frameworks rather than through classical stepwise growth, providing a kinetically efficient route to higher‐order structural complexity and organization. These results establish the integration of conformational adaptivity with cage isomerization pathways as a general design principle for multi‐stimuli‐responsive supramolecular systems in water.

Metal nitrene transfer catalysis is an efficient method for the direct formation of C─N bonds, but currently requires prefunctionalized, hazardous nitrene precursors. To expand the use of metal nitrene transfer catalysis, a method that generates the desired metal nitrene intermediate from an unfunctionalized nitrogen source is imperative. In this work, we demonstrate that a cobalt nitrene intermediate can be generated from 4‐phenylbutylamine under electrochemically oxidative conditions, supported by electron paramagnetic resonance (EPR) and high‐resolution mass spectrometry (HR‐MS) measurements. Constant potential electrolysis allowed C─H amination of 4‐phenylbutylamine to 2‐phenylpyrroline, a cyclic imine, formed via oxidation of 2‐phenylpyrrolidine. This method provides proof of principle to unlock the use of unfunctionalized amines as nitrene precursor alternatives, thereby extending the applicability of metal nitrene transfer catalysis .

The valorization of CO₂ waste into useful materials is a key endeavor in the field of sustainable chemistry. Molecular catalysts that convert CO₂ to CO through electrochemical reduction are difficult to optimize because of scaling relations known as "the iron law". This law states that electronic tuning to decrease activation barriers inevitably slows the overall catalytic reaction. Here, ditopic pyridine building blocks for M₁₂L₂₄ supramolecular cages are modified with mixed moieties to prepare a supramolecular cage that preorganizes FeCl-tetraphenylporphyrin catalysts, a proton source, and CO₂-adduct stabilizing moieties in close proximity. These cages are investigated by cyclic voltammetry (CV), which reveals that high local concentrations impact the CV catalytic response in a manner that aligns with modulation of important intermediates in the accepted catalytic mechanism. Enclosing multiple porphyrins in the cage facilitates comproportionation reactions, enhancing catalytic rates compared to an isoelectronic benchmark catalyst. The combination of both phenol and guanidinium moieties produces a system with an enhanced catalytic rate as compared to a molecular FeTPP analogue, while performing the CO₂RR at milder overpotentials (120 ΔmV). Relying on the combination of mechanistic understanding and robust self-assembly strategies, this work illustrates the strategic formulation of appropriate components to tailor the functional nanospace around an artificial active site.

CO₂ hydrogenation to methanol is achieved by homogeneous catalysts through a formic acid derivative. Previous studies have focused on using large amounts of additives to activate this intermediate, such as strong acids, amines and alcohols. Hydrogenation of CO₂ under basic conditions has been reported to only produce highly stable formate salts. We present in this contribution a novel method for formate activation that allows for CO₂ hydrogenation to methanol under basic conditions, by bimetallic activation of the formate salt by a cobalt and a nickel complex. From various catalytic and stoichiometric experiments, we propose that the nickel catalyst binds the in situ-generated formate to activate it for intramolecular cobalt hydride transfer, leading to an intermediate that can be further hydrogenated to methanol. This strategy could open new avenues in CO₂ hydrogenation under basic conditions, with implications for both homogeneously and heterogeneously catalyzed processes.

Stereochemistry plays a crucial role in how molecules interact with complex physiological environments, affecting pharmacokinetics, pharmacodynamics, efficacy, and toxicity. Although these effects are well studied for small-molecular drugs, they are largely overlooked for supramolecular assemblies used in drug delivery. Even for lipid nanoparticles (LNPs)—the most advanced RNA delivery platform—stereochemical effects are rarely investigated and, when considered, are typically limited to the ionizable lipid rather than the overall stereochemical identity of the LNP. Here we separate the ionizable lipid cKK-E12 into its two stereoisomers ( trans : R,S / S,R ; cis : R,R / S,S ), which are normally used as a mixture. LNPs containing the cis isomer exhibit improved physicochemical properties, stability, and protein expression. By systematically varying the stereochemistry of the ionizable lipid, phospholipid, and cholesterol, we reveal stereochemistry-dependent differences in uptake and protein expression across six cell lines and in vivo in zebrafish embryos and mice. AI-assisted cryo-TEM analysis and SAXS link enhanced protein expression to structural differences, demonstrating control over internal lipid phases (lamellar and inverse hexagonal), influencing sample uniformity, and identifying stereochemical identity as a key determinant of functional RNA delivery.