The motivation for the review stems from well-documented shortcomings in the current generation of delivery platforms. Lipid nanoparticles, which rose to global prominence through mRNA vaccines, offer good biocompatibility and high transfection efficiency but are rapidly cleared by the reticuloendothelial system, limiting their targeting capability. Polymeric carriers such as PLGA allow controlled degradation rates yet frequently suffer from burst release, making sustained, stable dosing difficult. Inorganic nanocarriers like mesoporous silica nanoparticles achieve high drug loading and stability but degrade poorly, raising long-term toxicity concerns. Biologically derived systems such as exosomes possess natural targeting properties and low immunogenicity, but their complex extraction, purification and low production yields hinder large-scale use. Beyond these material-specific flaws, the authors note that existing platforms still struggle with targeting recognition, circulation stability, cellular uptake and tissue penetration, particularly against the hostile and heterogeneous terrain of solid tumors.

What distinguishes assembly-based delivery is the way it exploits weak intermolecular forces—hydrogen bonding, electrostatic interactions, pi-pi stacking, van der Waals forces and hydrophobic effects—as programmable design tools rather than incidental chemistry. The review organizes the field’s construction principles into four synergistic mechanisms. Thermodynamic driving promotes the spontaneous formation of ordered structures as systems minimize free energy, with entropy-driven strategies such as evaporation-induced self-assembly producing long-range ordered films and hydrophobic effects combined with DNA origami achieving sub-nanometer positioning precision. Molecular recognition imparts specificity through DNA base pairing, antigen-antibody binding, host-guest chemistry and metal-ligand coordination, the latter enabling precise synthesis of porous frameworks such as metal-organic frameworks and covalent organic frameworks.

The remaining two mechanisms push self-assembly beyond static equilibrium. External regulation introduces electric, optical, magnetic and thermal fields, or chemical perturbations of pH, ionic strength and solvent polarity, to steer assembly pathways and enable reversible structural reconfiguration. The authors highlight pH-responsive supramolecular polymers that assemble and disassemble within milliseconds, ideal for rapid sensing, as well as magnetic fields that guide iron oxide nanoparticles into ordered arrangements for adaptive optical components. Kinetic control, the fourth mechanism, deliberately manipulates energy-evolution pathways and intermediate states rather than settling for thermodynamically stable end products. Perhaps most strikingly, the review describes how deep learning models such as AlphaFold2, originally built for protein structure prediction, are now being extended to the rational design of self-assembling peptide sequences, dramatically shortening high-throughput screening cycles and revealing kinetic assembly pathways previously inaccessible to conventional methods.

The building blocks available to designers are equally diverse. Peptides and proteins remain cornerstone materials: peptide nanofibers serve as carriers for synergistic tumor chemotherapy, stimuli-responsive peptide hydrogels support cartilage and neural tissue regeneration, and antimicrobial peptides self-assemble into nanofibrous traps that capture and destroy pathogens. Serum albumins co-assembled with PLGA yield supraparticles with enhanced encapsulation efficiency, while a nanoadaptor platform based on an Fc gamma receptor 1-albumin fusion protein enables non-covalent antibody immobilization for multi-specific nanobodies in immunotherapy. Natural and synthetic polyelectrolytes—chitosan, dextran sulfate, hyaluronic acid, polylysine and polyethylene glycol—contribute electrostatically driven assembly, improved drug solubility and biodegradability. Natural bioactive compounds add a remarkable twist: plant-derived molecules such as curcumin, ginsenoside Rg3 and berberine can self-assemble directly into therapeutic nanostructures through pi-pi stacking, amphiphilic balance or electrostatic interactions, producing carrier-free formulations. Supramolecular solvents, formed by the self-assembly of amphiphilic molecules into dynamic, stimulus-responsive nanostructures, round out the toolkit by boosting drug solubility, stability and membrane permeation.

On the delivery side, the review classifies assembly-based platforms into six strategies governed by a structure-function-behavior coupling paradigm. Passive targeting exploits the enhanced permeability and retention effect, in which leaky tumor vasculature and impaired lymphatic drainage allow appropriately sized nanoparticles to accumulate in tumor interstitium; recent work shows lipid nanoparticles with reduced size, near-neutral surface charge and shorter PEG-lipid acyl chains deliver mRNA more efficiently. Active targeting functionalizes carriers with ligands such as folic acid or antibodies that bind receptors overexpressed on target cells, a strategy validated in oral squamous cell carcinoma models using folate-decorated carriers loaded with the inhibitor JQ1, and extended to brain delivery with ionizable lipids that cross the blood-brain barrier. Stimuli-responsive release adds spatiotemporal control, with pH, temperature, enzyme, redox and magnetic triggers enabling on-demand payload release; one dual-responsive system exploits glutathione and esterase activity inside tumor cells to break redox balance for enhanced therapy.

The remaining strategies push boundaries further. Cell-mediated delivery co-opts the innate homing ability of macrophages and dendritic cells, with examples including macrophage-hitchhiking nanomedicines for tumor transport and inflammation-activated macrophage prodrug systems that cross the blood-brain barrier to treat meningitis. Physically assisted delivery deploys ultrasound, electric and magnetic fields to enhance penetration and accumulation, illustrated by biomimetic nanomedicines paired with ultrasound to overcome physiological barriers, a battery-free nanofluidic delivery patch that adheres to organ surfaces, and magnetic nanorobots that actively navigate to tumors for chemodynamic therapy. Combined delivery integrates multiple mechanisms—exemplified by a curcumin-bifidobacteria co-delivery system for multi-target intervention in type 2 diabetes and polymeric nanoparticles simultaneously loading an oxaliplatin prodrug and mitochondria-targeting peptides—pointing toward personalized, intelligent and multifunctional platforms.

Applications now span far beyond oncology. In tissue engineering, self-assembling peptide nanofibers sustain pro-angiogenic factor release after myocardial infarction while inhibiting cardiomyocyte apoptosis and fibrosis; liposome-GelMA hydrogels spatially segregate tetrahydrocurcumin and hepatocyte growth factor for synergistic skin wound repair; and matrix-metalloproteinase-responsive hydrogels co-assembling VEGF-mimetic and cleavable peptides reconstruct neurovascular networks after ischemic brain injury. In gene editing, virus-like particles deliver CRISPR-Cas9, base editors and prime editors as ribonucleoprotein complexes, avoiding genomic integration risks, while protein nanoparticle platforms achieve cytosolic co-delivery of nucleic acids, proteins and editing tools with efficiencies reaching 25.4 percent in murine lung epithelial cells. Even environmental science benefits: assembled hollow nitrogen-rich carbon plates accelerate persulfate-based water purification, metallic-phase transition metal dichalcogenide nanosheets remove lead from contaminated water, and phage-nanoparticle hybrids eliminate antibiotic-resistant bacteria with high specificity.

The authors are candid about the obstacles standing between laboratory promise and clinical reality. Standardization is lacking: research groups use divergent protocols for measuring drug loading, encapsulation efficiency and structural stability, undermining data comparability. Clinical validation remains thin, with most evidence limited to cell studies and small-animal models showing only short-term tumor suppression rather than long-term efficacy. Safety assessment focuses heavily on acute toxicity while immunogenicity, organ accumulation and the metabolic fate of degradation products remain poorly characterized. Regulatory hurdles compound the problem, as novel carriers lack unified evaluation standards and agencies demand extensive chronic toxicology data that lengthen timelines and inflate costs. Scalability presents its own challenges, since assembly systems exquisitely sensitive to raw-material purity, pH and temperature can degrade significantly in performance during industrial scale-up, and complex manufacturing processes keep production economically unviable for many designs.

Looking forward, the review charts a roadmap built on multi-stimuli strategies such as redox dual-responsiveness for cascade drug activation within the tumor microenvironment, multimodal theranostic platforms combining targeting, imaging and co-delivery, and the integration of artificial intelligence and big data into drug design and process optimization. Standardized evaluation frameworks, continuous automated manufacturing and interdisciplinary collaboration are identified as priorities for accelerating translation. If those pieces come together, the authors conclude, assembly-based delivery systems are positioned to evolve from elegant laboratory curiosities into the intelligent, efficient backbone of precision medicine, carrying the next generation of drugs, genes and proteins precisely where the body needs them most.

Subject of Research: Assembly-based delivery systems for targeted transport of drugs, genes and proteins in biomedical engineering

Article Title: Assembly delivery of bioactive matters: Advances, challenges, and prospects

Article References: Hu, Y., Zhong, L., Wang, P., Zhan, J., Yang, W., Qiu, X., & Hou, H. (2026). Assembly delivery of bioactive matters: Advances, challenges, and prospects. Journal of Advanced Research, 87, 963-987. https://doi.org/10.1016/j.jare.2025.12.019

Image Credits: AI Generated

DOI: 10.1016/j.jare.2025.12.019

Keywords: drug delivery, self-assembly, nanoparticles, targeted therapy, stimuli-responsive materials, peptide hydrogels, lipid nanoparticles, tissue engineering, gene editing delivery, supramolecular chemistry, theranostics, biocompatibility

The concept of a secondary building unit is familiar to anyone who has followed the evolution of framework chemistry. In metal–organic frameworks, clusters of metal ions bridged by organic linkers act as rigid, geometrically predictable joints. Because each node presents a fixed number of connection points arranged in a defined geometry, chemists can link them with linear or angular ligands and predict the topology of the resulting network. Connectivity, in this sense, is the key design variable: the more connection points a node offers, the more complex and topologically rich the network it can support. Achieving high connectivity with purely organic, non-metal nodes has long been difficult, because molecular clusters held together only by weak interactions tend to fall apart or rearrange during crystallization.

The new study tackles that challenge by turning to ionic clusters. These are aggregates in which charged organic building blocks associate through strong electrostatic attractions, often reinforced by networks of hydrogen bonds, to form discrete, well-defined assemblies that behave like single structural units. Rather than relying on a metal center to fix the geometry, the cluster’s charge distribution and directional ionic pairing lock its shape. When such a cluster carries a high number of available charged sites around its perimeter, it can bind many counter-charged organic partners simultaneously, functioning exactly like the multi-connected nodes of traditional framework chemistry while remaining entirely metal-free.

What emerges from this strategy is a crystalline porous organic salt: a material in which positively and negatively charged organic components assemble into an ordered lattice whose architecture is governed by electrostatic complementarity. The authors show that using ionic clusters as high-connectivity nodes produces frameworks with far greater structural complexity than could be achieved from simple ion pairs. The high connectivity translates directly into richer topologies and, crucially, into structures whose pores survive the removal of guest molecules from the crystal. That permanence is the defining requirement for useful porous materials, since a framework that collapses when emptied cannot capture, separate, or store anything.

The physics behind the stability is worth unpacking. In ordinary organic salts, each ion typically partners with just one or a few counterions, and the resulting crystals can be fragile, prone to phase transitions, and sensitive to humidity or solvent exchange. In an ionic cluster built from multiple charged units, the electrostatic charges are effectively distributed and multiply bridged. Each ionic contact reinforces the others, and the cluster presents a cohesive, internally satisfied structure to the outside world. At the same time, the outward-facing charged groups remain available for assembly. The result is a node that is simultaneously stable on the inside and reactive on the outside, precisely the combination needed for reliable crystallization into open frameworks.

Porous organic salts as a class carry distinct advantages over their covalent and coordination-based cousins. Their synthesis is often a matter of simple mixing in solution, with no need for solvothermal conditions, metal precursors, or elaborate catalysts. The components are frequently derived from abundant, inexpensive organic acids and bases. Because no metal is involved, the materials avoid issues of metal cost, toxicity, and scarcity that can complicate applications in water treatment or biomedicine. And because ionic frameworks are inherently charged, they offer strong, tunable electrostatic fields inside their pores, an attribute of particular interest for capturing carbon dioxide, whose quadrupolar charge distribution responds strongly to polar pore environments, and for separating similarly sized molecules that differ in polarity.

The introduction of high-connectivity ionic clusters addresses what has arguably been the field’s most serious limitation: topological simplicity. When the building blocks of an organic salt connect at only two or three points, the achievable network types are limited, and the resulting pores tend to be small, one-dimensional, or easily blocked by interpenetration. High-connectivity nodes change the calculus dramatically. With four, six, or more bonding directions available from a single node, designers can target three-dimensional pore networks with large cavities, intersecting channels, and controlled pore apertures. The study’s demonstration that such connectivity can be achieved through purely ionic assembly suggests that the design principles matured for metal–organic frameworks can now be ported into the metal-free world.

The implications extend across several application domains. In carbon capture, charged pore surfaces can be tuned to bind carbon dioxide preferentially over nitrogen, and a crystalline salt whose pore chemistry is dictated by interchangeable counterions offers a natural knob for optimization. In gas separation, the combination of size-selective apertures and strong electrostatic fields could discriminate between molecules that conventional adsorbents struggle to distinguish. In proton conduction, hydrated ionic frameworks are natural candidates for electrolyte membranes in fuel cells, since the same ionic pathways that define the structure can also transport charge. And in sensing and drug delivery, the ability to exchange guests within a stable, water-tolerant crystalline host makes these salts attractive platforms for uptake and release studies.

There are also fundamental scientific payoffs. Framework chemistry has long been organized around a handful of canonical secondary building units whose geometries dictate network topology. Adding ionic clusters to that catalog expands the mathematical space of achievable structures and raises new questions about how charge delocalization, hydrogen bonding, and counterion identity shape crystallization outcomes. The work also highlights a conceptual bridge between solution-phase supramolecular chemistry and solid-state materials design: the same electrostatic forces that assemble ions into discrete clusters in solution can be harnessed, under the right conditions, to assemble those clusters into extended, permanently porous crystals. Understanding and controlling that hierarchy, from ion to cluster to framework, is a central theme of modern supramolecular materials science.

Challenges remain before such materials reach practical deployment. Water sensitivity, long a weakness of ionic solids, must be quantified and, where necessary, engineered away through hydrophobic pore linings or reinforced ionic networks. Scalability of synthesis, reproducibility of crystal quality, and long-term stability under cycling conditions all require systematic study. Yet the demonstration that ionic clusters can serve as reliable high-connectivity secondary building units represents a genuine conceptual advance, giving chemists a metal-free, solution-processable route to complex porous architectures. As the toolkit of ionic nodes grows, crystalline porous organic salts may move from a laboratory curiosity to a serious competitor in the crowded field of functional porous materials, proving that the humble electrostatic bond, when organized with sufficient geometric ambition, can build structures as sophisticated as any forged from metal or covalent links.

Subject of Research: Use of ionic clusters as high-connectivity secondary building units for constructing crystalline porous organic salts.

Article Title: Ionic clusters as high-connectivity secondary building units for crystalline porous organic salts

Article References: Lu, Y.-L., Chen, Y., Qu, H., Zhang, L., O’Shaughnessy, M., Fellowes, T., & Cooper, A. I. (2026). Ionic clusters as high-connectivity secondary building units for crystalline porous organic salts. Nature Chemistry. https://doi.org/10.1038/s41557-026-02248-w

Image Credits: AI Generated

DOI: 10.1038/s41557-026-02248-w

Keywords: ionic clusters, porous organic salts, secondary building units, crystalline frameworks, metal-free materials, supramolecular chemistry, porosity, carbon capture, gas separation, framework chemistry, electrostatic assembly, hydrogen bonding

Schwarzites are named after Hermann Schwarz, the 19th-century German mathematician who first described these intriguing periodic minimal surfaces characterized by intricate curvature and large surface area combined with remarkably low density. Despite their appealing mathematical elegance and theoretical allure, the physical synthesis of schwarzites has proven elusive. Unlike more familiar carbon nanostructures such as graphene and carbon nanotubes, schwarzites feature a complex arrangement of polygons that create a saddle-shaped, negatively curved surface. This inherent geometric complexity has posed a formidable challenge to chemists attempting to assemble such structures from sp²-hybridized carbon atoms.

Professor Würthner’s team has developed an innovative supramolecular approach to tackle this challenge, leveraging the unique properties of nanographene molecules incorporating heptagonal rings. Whereas standard graphene is composed purely of hexagonal carbon rings generating flat sheets, the introduction of heptagons induces curvature, creating the negative Gaussian curvature that is the hallmark of schwarzite structures. This method was recently demonstrated through assembling nanographene units around C60 fullerenes, achieving schwarzite-like arrangements exhibiting the targeted three-dimensional architecture.

A central element of this endeavor is the polymerization of these heptagon-containing nanographene building blocks into extended three-dimensional pi-conjugated frameworks. By advancing the synthetic sophistication of these components and fine-tuning their chemical environment, the research seeks to generate bulk schwarzite materials that embody the theorized electronic and mechanical properties. Such materials could offer exceptional electrical conductivity due to their fully delocalized electron systems spanning multiple dimensions, a feat unachieved by planar graphene or tubular nanotubes.

From a physical standpoint, schwarzites distinguish themselves through their unique topological electronic characteristics. Theorists predict that certain schwarzite lattices host Dirac cones—linear energy-momentum dispersions that are foundational to phenomena such as high electron mobility and exotic quantum phases of matter. If experimentally realized, these properties could unlock new physics and potential applications in quantum materials and electronic devices, positioning schwarzites as the next frontier for carbon-based nanotechnology.

The University of Würzburg’s Center for Nanosystems Chemistry, under Würthner’s leadership, is at the heart of this ambitious project. The center benefits from cutting-edge instrumentation and advanced facilities, courtesy of prior investments by the Free State of Bavaria. These resources will facilitate detailed characterization of newly synthesized schwarzites, ranging from structural analysis via electron microscopy to probing electronic behavior through spectroscopic methods. Understanding structure-property relationships in such novel materials is essential to harness their potential for practical applications.

This ERC-funded project represents Würthner’s second Advanced Grant, underscoring his position as a leading figure in organic and supramolecular chemistry. His earlier grant supported pioneering work in artificial photosynthesis, focusing on developing catalysts capable of splitting water molecules efficiently to produce clean hydrogen fuel. That success demonstrates his team’s capacity to address major scientific challenges by melding fundamental chemistry with visionary technological goals.

Würthner’s strategic approach integrates molecular design, supramolecular assembly, and polymer chemistry, pushing the boundary where synthetic chemistry meets materials science. By meticulously controlling the molecular architecture of nanographenes and their assembly into three-dimensional networks, the research aims to fabricate schwarzites with customizable properties. Such control over curvature and electronic conjugation could herald a new class of carbon materials tailored for specific applications in energy, filtration, and electronics.

The implications of successfully synthesizing schwarzites extend far beyond academic curiosity. Porous three-dimensional carbon frameworks with superior electrical conductivity and stability may revolutionize battery electrodes by enhancing charge transport and enabling faster ion diffusion. Similarly, their large internal surface area combined with tunable chemical functionality could make them ideal candidates for selective gas separation or water purification systems, addressing urgent environmental needs.

Yet, despite these exciting prospects, challenges remain immense. The synthetic routes to carefully incorporate heptagonal defects into extended carbon networks must be exquisitely precise to ensure desired curvature and connectivity. Additionally, ensuring the scalability and reproducibility of such complex materials will be crucial for transitioning from laboratory samples to practical technological components.

Professor Würthner’s vision exemplifies the synergy between mathematical theory and chemical innovation. By translating Schwarz’s 19th-century geometric abstractions into real, functional materials, this project blurs the boundary between abstract science and applicative technology. The successful realization of schwarzite materials would not only validate decades of theoretical predictions but also open transformative pathways in nanomaterial design and functional carbon architectures.

As the SCHWARZITE project unfolds over the coming five years, the scientific community will keenly watch Würthner’s progress. With robust ERC funding and a pioneering research team, the prospects for overcoming longstanding obstacles to schwarzite synthesis have never looked more promising. This work heralds a new era in carbon nanomaterials, potentially reshaping technologies across sectors from sustainable energy to environmental remediation.

In sum, Professor Frank Würthner’s ERC-funded pursuit of schwarzite carbon materials epitomizes cutting-edge research at the interface of chemistry, physics, and materials science. Harnessing molecular design and supramolecular chemistry, his project aspires to manifest exotic carbon allotropes long confined to mathematical theory into the tangible realm of high-performance nanomaterials. Their realization would mark a milestone in carbon materials science, paving the way for unprecedented technological innovations.

Subject of Research:
Synthesis and characterization of schwarzite carbon nanomaterials through supramolecular chemistry approaches for advanced energy and filtration applications.

Article Title:
Professor Frank Würthner’s Quest to Synthesize Schwarzite Carbon Nanostructures Powered by ERC Advanced Grant

News Publication Date:
Not provided

Web References:
https://mediasvc.eurekalert.org/Api/v1/Multimedia/43b03666-166c-477c-949e-8eb612c9e6af/Rendition/low-res/Content/Public

Image Credits:
Christoph Weiss / University of Würzburg

Keywords

Supramolecular chemistry, Nanostructures, Carbon allotropes