Chemical and Biomolecular Engineering - Research Publications

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    Metal–Phenolic‐Mediated Assembly of Functional Small Molecules into Nanoparticles: Assembly and Bioapplications
    Chen, J ; Cortez‐Jugo, C ; Kim, C ; Lin, Z ; Wang, T ; De Rose, R ; Xu, W ; Wang, Z ; Gu, Y ; Caruso, F (Wiley, 2024-03-18)
    Abstract Small molecules, including therapeutic drugs and tracer molecules, play a vital role in biological processing, disease treatment and diagnosis, and have inspired various nanobiotechnology approaches to realize their biological function, particularly in drug delivery. Desirable features of a delivery system for functional small molecules (FSMs) include high biocompatibility, high loading capacity, and simple manufacturing processes, without the need for chemical modification of the FSM itself. Herein, we report a simple and versatile approach, based on metal–phenolic‐mediated assembly, for assembling FSMs into nanoparticles (i.e., FSM‐MPN NPs) under aqueous and ambient conditions. We demonstrate loading of anticancer drugs, latency reversal agents, and fluorophores at up to ~80 % that is mostly facilitated by π and hydrophobic interactions between the FSM and nanoparticle components. Secondary nanoparticle engineering involving coating with a polyphenol–antibody thin film or sequential co‐loading of multiple FSMs enables cancer cell targeting and combination delivery, respectively. Incorporating fluorophores into FSM‐MPN NPs enables the visualization of biodistribution at different time points, revealing that most of these NPs are retained in the kidney and heart 24 h post intravenous administration. This work provides a viable pathway for the rational design of small molecule nanoparticle delivery platforms for diverse biological applications.
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    Metal-Phenolic-Mediated Assembly of Functional Small Molecules into Nanoparticles: Assembly and Bioapplications
    Chen, J ; Cortez-Jugo, C ; Kim, C-J ; Lin, Z ; Wang, T ; De Rose, R ; Xu, W ; Wang, Z ; Gu, Y ; Caruso, F (WILEY-V C H VERLAG GMBH, 2024-03-18)
    Small molecules, including therapeutic drugs and tracer molecules, play a vital role in biological processing, disease treatment and diagnosis, and have inspired various nanobiotechnology approaches to realize their biological function, particularly in drug delivery. Desirable features of a delivery system for functional small molecules (FSMs) include high biocompatibility, high loading capacity, and simple manufacturing processes, without the need for chemical modification of the FSM itself. Herein, we report a simple and versatile approach, based on metal-phenolic-mediated assembly, for assembling FSMs into nanoparticles (i.e., FSM-MPN NPs) under aqueous and ambient conditions. We demonstrate loading of anticancer drugs, latency reversal agents, and fluorophores at up to ~80 % that is mostly facilitated by π and hydrophobic interactions between the FSM and nanoparticle components. Secondary nanoparticle engineering involving coating with a polyphenol-antibody thin film or sequential co-loading of multiple FSMs enables cancer cell targeting and combination delivery, respectively. Incorporating fluorophores into FSM-MPN NPs enables the visualization of biodistribution at different time points, revealing that most of these NPs are retained in the kidney and heart 24 h post intravenous administration. This work provides a viable pathway for the rational design of small molecule nanoparticle delivery platforms for diverse biological applications.
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    Engineering poly(ethylene glycol) particles for targeted drug delivery
    Li, S ; Ma, Y ; Cui, J ; Caruso, F ; Ju, Y (ROYAL SOC CHEMISTRY, 2024-02-29)
    Poly(ethylene glycol) (PEG) is considered to be the "gold standard" among the stealth polymers employed for drug delivery. Using PEG to modify or engineer particles has thus gained increasing interest because of the ability to prolong blood circulation time and reduce nonspecific biodistribution of particles in vivo, owing to the low fouling and stealth properties of PEG. In addition, endowing PEG-based particles with targeting and drug-loading properties is essential to achieve enhanced drug accumulation at target sites in vivo. In this feature article, we focus on recent work on the synthesis of PEG particles, in which PEG is the main component in the particles. We highlight different synthesis methods used to generate PEG particles, the influence of the physiochemical properties of PEG particles on their stealth and targeting properties, and the application of PEG particles in targeted drug delivery.
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    Tracking the Endosomal Escape of Nanoparticles in Live Cells Using a Triplex-Forming Oligonucleotide
    Bhangu, SK ; Mummolo, L ; Fernandes, S ; Amodio, A ; Radziwon, A ; Dyett, B ; Savioli, M ; Mantri, N ; Cortez-Jugo, C ; Caruso, F ; Cavalieri, F (Wiley, 2024)
    Nanoparticle-mediated intracellular delivery of oligonucleotides is a complex phenomenon that depends on the architecture and the intracellular trafficking of the engineered nanoparticles. Unravelling the molecular arrangements of oligonucleotides within the nanoparticles as well as their intracellular behavior are essential for designing effective nucleic acid delivery systems. Herein, a simple and general strategy for probing the endosomal escape of nanoparticles carrying oligonucleotides in live cells is reported. A triplex-forming oligonucleotide probe is designed to target the transcription factor, kappa-light-chain-enhancer of activated B cells (NF-κB), in the cytosol of cells and to transduce the binding into a fluorescent Förster resonance energy transfer (FRET) signal. The combined use of the triplex-forming oligonucleotide probe and super-resolution microscopy enables the elucidation of the morphology, intracellular localization, and endosomal escape of the oligonucleotide-loaded nanoparticles on a molecular level and with nanoscale resolution. The co-delivery of the FRET probe and mRNA in cells via lipid- and polymer- based nanoparticles allow simultaneous correlation of the endosomal escape properties of nanoparticles and gene expression efficiency.
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    Emerging Strategies for Immunotherapy of Solid Tumors Using Lipid-Based Nanoparticles
    Fernandes, S ; Cassani, M ; Cavalieri, F ; Forte, G ; Caruso, F (WILEY, 2024-02)
    The application of lipid-based nanoparticles for COVID-19 vaccines and transthyretin-mediated amyloidosis treatment have highlighted their potential for translation to cancer therapy. However, their use in delivering drugs to solid tumors is limited by ineffective targeting, heterogeneous organ distribution, systemic inflammatory responses, and insufficient drug accumulation at the tumor. Instead, the use of lipid-based nanoparticles to remotely activate immune system responses is an emerging effective strategy. Despite this approach showing potential for treating hematological cancers, its application to treat solid tumors is hampered by the selection of eligible targets, tumor heterogeneity, and ineffective penetration of activated T cells within the tumor. Notwithstanding, the use of lipid-based nanoparticles for immunotherapy is projected to revolutionize cancer therapy, with the ultimate goal of rendering cancer a chronic disease. However, the translational success is likely to depend on the use of predictive tumor models in preclinical studies, simulating the complexity of the tumor microenvironment (e.g., the fibrotic extracellular matrix that impairs therapeutic outcomes) and stimulating tumor progression. This review compiles recent advances in the field of antitumor lipid-based nanoparticles and highlights emerging therapeutic approaches (e.g., mechanotherapy) to modulate tumor stiffness and improve T cell infiltration, and the use of organoids to better guide therapeutic outcomes.
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    Engineering Antimicrobial Metal-Phenolic Network Nanoparticles with High Biocompatibility for Wound Healing.
    Yu, R ; Chen, H ; He, J ; Zhang, Z ; Zhou, J ; Zheng, Q ; Fu, Z ; Lu, C ; Lin, Z ; Caruso, F ; Zhang, X (Wiley, 2024-02)
    Antibiotic-resistant bacteria pose a global health threat by causing persistent and recurrent microbial infections. To address this issue, antimicrobial nanoparticles (NPs) with low drug resistance but potent bactericidal effects have been developed. However, many of the developed NPs display poor biosafety and their synthesis often involves complex procedures and the antimicrobial modes of action are unclear. Herein, a simple strategy is reported for designing antimicrobial metal-phenolic network (am-MPN) NPs through the one-step assembly of a seeding agent (diethyldithiocarbamate), natural polyphenols, and metal ions (e.g., Cu2+ ) in aqueous solution. The Cu2+ -based am-MPN NPs display lower Cu2+ antimicrobial concentrations (by 10-1000 times) lower than most reported nanomaterials and negligible toxicity across various models, including, cells, blood, zebrafish, and mice. Multiple antimicrobial modes of the NPs have been identified, including bacterial wall disruption, reactive oxygen species production, and quinoprotein formation, with the latter being a distinct pathway identified for the antimicrobial activity of the polyphenol-based am-MPN NPs. The NPs exhibit excellent performance against multidrug-resistant bacteria (e.g., methicillin-resistant Staphylococcus aureus (MRSA)), efficiently inhibit and destroy bacterial biofilms, and promote the healing of MRSA-infected skin wounds. This study provides insights on the antimicrobial properties of metal-phenolic materials and the rational design of antimicrobial metal-organic materials.
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    Cytoprotective Metal-Phenolic Network Sporulation to Modulate Microalgal Mobility and Division
    Li, X ; Liu, H ; Lin, Z ; Richardson, JJ ; Xie, W ; Chen, F ; Lin, W ; Caruso, F ; Zhou, J ; Liu, B (WILEY, 2024-01)
    Synthetic cell exoskeletons created from abiotic materials have attracted interest in materials science and biotechnology, as they can regulate cell behavior and create new functionalities. Here, a facile strategy is reported to mimic microalgal sporulation with on-demand germination and locomotion via responsive metal-phenolic networks (MPNs). Specifically, MPNs with tunable thickness and composition are deposited on the surface of microalgae cells via one-step coordination, without any loss of cell viability or intrinsic cell photosynthetic properties. The MPN coating keeps the cells in a dormant state, but can be disassembled on-demand in response to environmental pH or chemical stimulus, thereby reviving the microalgae within 1 min. Moreover, the artificial sporulation of microalgae resulted in resistance to environmental stresses (e.g., metal ions and antibiotics) akin to the function of natural sporulation. This strategy can regulate the life cycle of complex cells, providing a synthetic strategy for designing hybrid microorganisms.
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    Particle Engineering via Supramolecular Assembly of Macroscopic Hydrophobic Building Blocks
    Kim, C-J ; Goudeli, E ; Ercole, F ; Ju, Y ; Gu, Y ; Xu, W ; Quinn, JF ; Caruso, F (WILEY-V C H VERLAG GMBH, 2024-01-22)
    Tailoring the hydrophobicity of supramolecular assembly building blocks enables the fabrication of well-defined functional materials. However, the selection of building blocks used in the assembly of metal-phenolic networks (MPNs), an emerging supramolecular assembly platform for particle engineering, has been essentially limited to hydrophilic molecules. Herein, we synthesized and applied biscatechol-functionalized hydrophobic polymers (poly(methyl acrylate) (PMA) and poly(butyl acrylate) (PBA)) as building blocks to engineer MPN particle systems (particles and capsules). Our method allowed control over the shell thickness (e.g., between 10 and 21 nm), stiffness (e.g., from 10 to 126 mN m-1 ), and permeability (e.g., 28-72 % capsules were permeable to 500 kDa fluorescein isothiocyanate-dextran) of the MPN capsules by selection of the hydrophobic polymer building blocks (PMA or PBA) and by controlling the polymer concentration in the MPN assembly solution (0.25-2.0 mM) without additional/engineered assembly processes. Molecular dynamics simulations provided insights into the structural states of the hydrophobic building blocks during assembly and mechanism of film formation. Furthermore, the hydrophobic MPNs facilitated the preparation of fluorescent-labeled and bioactive capsules through postfunctionalization and also particle-cell association engineering by controlling the hydrophobicity of the building blocks. Engineering MPN particle systems via building block hydrophobicity is expected to expand their use.
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    YAP Signaling Regulates the Cellular Uptake and Therapeutic Effect of Nanoparticles
    Cassani, M ; Fernandes, S ; Oliver-De La Cruz, J ; Durikova, H ; Vrbsky, J ; Patočka, M ; Hegrova, V ; Klimovic, S ; Pribyl, J ; Debellis, D ; Skladal, P ; Cavalieri, F ; Caruso, F ; Forte, G (Wiley, 2023-11-09)
    Interactions between living cells and nanoparticles are extensively studied to enhance the delivery of therapeutics. Nanoparticles size, shape, stiffness, and surface charge are regarded as the main features able to control the fate of cell-nanoparticle interactions. However, the clinical translation of nanotherapies has so far been limited, and there is a need to better understand the biology of cell-nanoparticle interactions. This study investigates the role of cellular mechanosensitive components in cell-nanoparticle interactions. It is demonstrated that the genetic and pharmacologic inhibition of yes-associated protein (YAP), a key component of cancer cell mechanosensing apparatus and Hippo pathway effector, improves nanoparticle internalization in triple-negative breast cancer cells regardless of nanoparticle properties or substrate characteristics. This process occurs through YAP-dependent regulation of endocytic pathways, cell mechanics, and membrane organization. Hence, the study proposes targeting YAP may sensitize triple-negative breast cancer cells to chemotherapy and increase the selectivity of nanotherapy.
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    Engineering Metal-Phenolic Network Nanoparticles via Microfluidics
    Chen, J ; Spoljaric, S ; Calatayud-Sanchez, A ; Alvarez-Brana, Y ; Caruso, F (AMER CHEMICAL SOC, 2023-10-09)
    Microfluidics opens new avenues for materials engineering, as it enables scalable synthesis and provides highly controllable environments for reactions. Herein, we leverage microfluidics to engineer the properties of (bioactive) metal-phenolic network nanoparticles (MPN NPs), an emerging and highly modular nanoparticle platform for the incorporation and delivery of bioactive cargo. By varying the microfluidics operating parameters (flow rate ratio, total flow rate, temperature) and NP composition, we assemble MPN NPs, which consist of poly(ethylene glycol), biomacromolecules, metal ions, and polyphenols. Compared to MPN NPs prepared via bulk assembly, the microfluidics-assembled MPN NPs possess a broader tunable size range (i.e., ∼40-330 nm vs ∼45-220 nm for bulk-assembled NPs) and a higher (by ∼30%) protein loading. The bulk-assembled MPN NPs show pH-responsive protein release behavior (e.g., ∼50% at pH 7; ∼25% at pH 9; 48 h). Likewise, the MPN NPs prepared via microfluidics at a flow rate ratio of 1:1 display similar pH-responsive protein release behavior. For the microfluidics-assembled MPN NPs, protein release is also dependent on temperature (e.g., 30% at 4 °C, and ∼50% at 20 and 37 °C). Furthermore, assembly at a 1:1 flow rate ratio overall enables greater tunability of protein release profiles than that at higher flow rate ratios. While bulk-assembled NPs display a higher degree of cell association, NPs assembled via both strategies can be internalized by cells after 24 h. These findings provide new insights into engineering the properties of metal-organic materials via microfluidics, which is expected to advance their development and application.