Thermo-Responsive Polymer-siRNA Conjugates Enabling Artificial Control of Gene Silencing around Body Temperature.

Purpose: Controlling small interfering RNA (siRNA) activity by external stimuli is useful to exert a selective therapeutic effect at the target site. This study aims to develop a technology to control siRNA activity in a thermo-responsive manner, which can be utilized even at temperatures close to body temperature.

Methods: siRNA was conjugated with a thermo-responsive copolymer that was synthesized by copolymerization of N-isopropylacrylamide (NIPAAm) and hydrophilic N,N-dimethylacrylamide (DMAA) to permit thermally controlled interaction between siRNA and an intracellular gene silencing-related protein by utilizing the coil-to-globule phase transition of the copolymer.

Anti-Inflammatory Therapy for Temporomandibular Joint Osteoarthritis Using mRNA Medicine Encoding Interleukin-1 Receptor Antagonist.

Messenger RNA (mRNA) is an emerging drug modality for protein replacement therapy. As mRNA efficiently provides protein expression in post-mitotic cells without the risk of insertional mutagenesis, direct delivery of mRNA can be applied, not only as an alternative to gene therapy, but also for various common diseases such as osteoarthritis (OA). In this study, using an mRNA-encoding interleukin-1 receptor antagonist (IL-1Ra), we attempted anti-inflammatory therapy in a rat model of the temporomandibular joint (TMJ) OA, which causes long-lasting joint pain with chronic inflammation.

Bioresponsive Polymers for Nanomedicine-Expectations and Reality!

Bioresponsive polymers in nanomedicine have been widely perceived to selectively activate the therapeutic function of nanomedicine at diseased or pathological sites, while sparing their healthy counterparts. This idea can be described as an advanced version of Paul Ehrlich's magic bullet concept. From that perspective, the inherent anomalies or malfunction of the pathological sites are generally targeted to allow the selective activation or sensory function of nanomedicine.

Cancerous pH-responsive polycarboxybetaine-coated lipid nanoparticle for smart delivery of siRNA against subcutaneous tumor model in mice.

Lipid nanoparticles (LNPs) have been commonly used as a vehicle for nucleic acids, such as small interfering RNA (siRNA); the surface modification of LNPs is one of the determinants of their delivery efficiency especially in systemic administration. However, the applications of siRNA-encapsulated LNPs are limited due to a lack effective systems to deliver to solid tumors. Here, we report a smart surface modification using a charge-switchable ethylenediamine-based polycarboxybetaine for enhancing tumor accumulation via interaction with anionic tumorous tissue constituents due to selective switching to cationic charge in response to cancerous acidic pH.

Nanocarriers escaping from hyperacidified endo/lysosomes in cancer cells allow tumor-targeted intracellular delivery of antibodies to therapeutically inhibit c-MYC.

Intracellular protein delivery is a powerful strategy for developing innovative therapeutics. Nanocarriers present great potential to deliver proteins inside cells by promoting cellular uptake and overcoming entrapment and degradation in acidic endo/lysosomal compartments. Thus, because cytosolic access is essential for eliciting the function of proteins, significant efforts have been dedicated to engineering nanocarriers with maximal endosomal escape regardless of the cell type.

New Advances in Biomedical Application of Polymeric Micelles.

In the last decade, nanomedicine has arisen as an emergent area of medicine, which studies nanometric systems, namely polymeric micelles (PMs), that increase the solubility and the stability of the encapsulated drugs. Furthermore, their application in dermal drug delivery is also relevant. PMs present unique characteristics because of their unique core-shell architecture.

A Hoechst Reporter Enables Visualization of Drug Engagement and : Toward Safe and Effective Nanodrug Delivery.

Assessment of drug activation and subsequent interaction with targets in living tissues could guide nanomedicine design, but technologies enabling insight into how a drug reaches and binds its target are limited. We show that a Hoechst-based reporter system can monitor drug release and engagement from a nanoparticle delivery system and , elucidating differences in target-bound drug distribution related to drug-linker and nanoparticle properties. Drug engagement is defined as chemical detachment of drug or reporter from a nanoparticle and subsequent binding to a subcellular target, which in the case of Hoechst results in a fluorescence signal.

Systemic single administration of anti-inflammatory microRNA 146a-5p loaded in polymeric nanomedicines with active targetability attenuates neointimal hyperplasia by controlling inflammation in injured arteries in a rat model.

Neointimal hyperplasia (NIH) after revascularization is a key unsolved clinical problem. Various studies have shown that attenuation of the acute inflammatory response on the vascular wall can prevent NIH. MicroRNA146a-5p (miR146a-5p) has been reported to show anti-inflammatory effects by inhibiting the NF-κB pathway, a well-known key player of inflammation of the vascular wall.

Effect of PEGylation on the Drug Release Performance and Hemocompatibility of Photoresponsive Drug-Loading Platform.

Coronary stenosis has been one of the most common heart diseases that drastically increases the risk of fatal disorders such as heart attack. Angioplasty using drug coated balloons (DCB) has been one of the most safe and promising treatments. To minimize the risk of thrombosis of such DCBs during intervention, a different approach that can secure high hemocompatibility under blood flow is necessary.

Antitumoral RNA-targeted oligonucleotide therapeutics: The third pillar after small molecule inhibitors and antibodies.

Oligonucleotide therapeutics, drugs consisting of 10-50 nucleotide-long single- or double-stranded DNA or RNA molecules that can bind to specific DNA or RNA sequences or proteins, include antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNAs (miRNAs), aptamers, and decoys. These oligonucleotide therapeutics could potentially become the third pillar of drug development. In particular, ASOs and siRNAs are advanced tools that are widely used to silence gene expression.

Size-tunable PEG-grafted copolymers as a polymeric nanoruler for passive targeting muscle tissues.

Muscle-targeted drug delivery is a major challenge in nanomedicine. The extravasation of nanomedicines (or nanoparticles) from the bloodstream into muscle tissues is hindered by the continuous endothelium, the so-called blood-muscle barrier. This study aimed to evaluate the optimal size of macromolecular drugs for extravasation (or passive targeting) into muscle tissues.

Microglial Immunoregulation by Apoptotic Cellular Membrane Mimetic Polymeric Particles.

Phosphatidylserine (PtdSer), one of the phospholipids that the apoptotic cell exposes, has emerged for anti-inflammatory therapy polarizing inflammatory microglia (Mi1) to anti-inflammatory phenotype (Mi2). In this study, we report microglia polarization effect of PtdSer-exposing polymeric particles (PSPs). PSPs upregulated Mi2 microglia and suppressed Mi1 microglia through peroxisome proliferator-activated receptor gamma upregulation and .

Accelerated Post-Polymerization Amidation of Polymers with Side-Chain Ester Groups by Intramolecular Activation.

The catalytic conversion of esters to amides represents new opportunities in the synthetic diversification and upcycling of polymers, as esters are commonly featured in various polymer structures. Yet, direct amidation is typically hampered by poor reaction kinetics and the effects of polymer structure on the reactivity remain poorly understood. We report the accelerated amidation for amines with additional hydrogen bond donating or accepting groups.

Changeable net charge on nanoparticles facilitates intratumor accumulation and penetration.

The Enhanced Permeability and Retention (EPR) effect is a golden strategy for the nanoparticle (NP)-based targeting of solid tumors, and the surface property of NPs might be a determinant on their targeting efficiency. Poly(ethylene glycol) (PEG) is commonly used as a shell material; however, it has been pointed out that PEG-coated NPs may exhibit accumulation near tumor vasculature rather than having homogenous intratumor distribution. The PEG shell plays a pivotal role on prolonged blood circulation of NPs but potentially impairs the intratumor retention of NPs.

Delivery Systems of Plasmid DNA and Messenger RNA for Advanced Therapies.

The vast potential of non-viral delivery systems of messenger RNA (mRNA) and plasmid DNA (pDNA) has been demonstrated in the vaccines against coronavirus disease 2019 (COVID-19) [...

Stabilization of bicelles using metal-binding peptide for extended blood circulation.

A metal-binding peptide appending cholic acid, Chol-MBP, formed bicelles by mixing with 1,2-dipalmitoyl--3-phosphorylcholine (DPPC). Coordination of Chol-MBP with Cu stabilized DPPC bicelles against dilution and contamination of serum proteins, enabling extended blood circulation. This study demonstrates an effective supramolecular design of phospholipid bicelles with enhanced stability useful for membrane-based biomaterials.

Targeted nanomedicine in cisplatin-based cancer therapeutics.

Since its license in 1978, cisplatin has proved to be one of the most successful chemotherapeutic agents in the world. However, two acute challenges facing cisplatin, resistance and toxicity, have resulted in a bottleneck of clinical application. Targeted nanomedicine shows great promise in delivering cisplatin for maximizing efficacy while minimizing off-target toxicity.

Recent advances in biomaterial-boosted adoptive cell therapy.

Adoptive immunotherapies based on the transfer of functional immune cells hold great promise in treating a wide range of malignant diseases, especially cancers, autoimmune diseases, and infectious diseases. However, manufacturing issues and biological barriers lead to the insufficient population of target-selective effector cells at diseased sites after adoptive transfer, hindering effective clinical translation. The convergence of immunology, cellular biology, and materials science lays a foundation for developing biomaterial-based engineering platforms to overcome these challenges.

Nanomedicine for brain cancer.

CNS tumors remain among the deadliest forms of cancer, resisting conventional and new treatment approaches, with mortality rates staying practically unchanged over the past 30 years. One of the primary hurdles for treating these cancers is delivering drugs to the brain tumor site in therapeutic concentration, evading the blood-brain (tumor) barrier (BBB/BBTB). Supramolecular nanomedicines (NMs) are increasingly demonstrating noteworthy prospects for addressing these challenges utilizing their unique characteristics, such as improving the bioavailability of the payloadsviacontrolled pharmacokinetics and pharmacodynamics, BBB/BBTB crossing functions, superior distribution in the brain tumor site, and tumor-specific drug activation profiles.

Cell-Penetrating Peptides: Emerging Tools for mRNA Delivery.

Messenger RNAs (mRNAs) were previously shown to have great potential for preventive vaccination against infectious diseases and therapeutic applications in the treatment of cancers and genetic diseases. Delivery systems for mRNAs, including lipid- and polymer-based carriers, are being developed for improving mRNA bioavailability. Among these systems, cell-penetrating peptides (CPPs) of 4-40 amino acids have emerged as powerful tools for mRNA delivery, which were originally developed to deliver membrane-impermeable drugs, peptides, proteins, and nucleic acids to cells and tissues.

Systemically Applicable Glutamine-Functionalized Polymer Exerting Multivalent Interaction with Tumors Overexpressing ASCT2.

Transporter ASCT2, which predominantly imports glutamine (Gln), is overexpressed in a variety of cancer cells, and targeting ASCT2 is expected to be a promising approach for tumor diagnosis and therapy. In this work, we designed a series of glutamine-modified poly(l-lysine) (PLys(Gln)) homopolymers and PEG-PLys(Gln) block copolymers and investigated their tumor-targeting abilities. With increasing degree of polymerization in the PLys(Gln) homopolymers, their cellular uptake was gradually enhanced through multivalent interactions with ASCT2.

Dynamic Stabilization of Unit Polyion Complexes Incorporating Small Interfering RNA by Fine-Tuning of Cationic Block Length in Two-Branched Poly(ethylene glycol)--poly(l-lysine).

To stabilize small interfering RNA (siRNA) in the bloodstream for systemic RNAi therapeutics, we previously fabricated ultrasmall siRNA nanocarriers that were sub-20 nm in hydrodynamic diameter, named as unit polyion complexes (uPICs), using two-branched poly(ethylene glycol)--poly(l-lysine) (bPEG-PLys). The blood retention time of uPICs is dramatically increased in the presence of free bPEG-PLys, suggesting dynamic stabilization of uPICs by free bPEG-PLys based on their equilibrium. Herein, we examined how the degree of polymerization of PLys (DP) affected the dynamic stability of uPICs in the bloodstream during prolonged circulation.

Cell Cycle Regulation and DNA Damage Response Networks in Diffuse- and Intestinal-Type Gastric Cancer.

Dynamic regulation in molecular networks including cell cycle regulation and DNA damage response play an important role in cancer. To reveal the feature of cancer malignancy, gene expression and network regulation were profiled in diffuse- and intestinal-type gastric cancer (GC). The results of the network analysis with Ingenuity Pathway Analysis (IPA) showed that the activation states of several canonical pathways related to cell cycle regulation were altered.

Sequentially Self-Assembled Nanoreactor Comprising Tannic Acid and Phenylboronic Acid-Conjugated Polymers Inducing Tumor-Selective Enzymatic Activity.

The construction of enzyme delivery systems, which can control enzymatic activity at a target site, is important for efficient enzyme-prodrug therapy/diagnosis. Herein we report a facile technique to construct a systemically applicable β-galactosidase (β-Gal)-loaded ternary complex comprising tannic acid (TA) and phenylboronic acid-conjugated polymers through sequential self-assembly in aqueous solution. At physiological conditions, the ternary complex exhibited a hydrodynamic diameter of ∼40 nm and protected the loaded β-Gal from unfavorable degradation by proteinase.