Enhanced mRNA delivery using ultrasound-delivered click reactive anchors.

Therapeutic nucleic acid delivery has many potential applications, but it remains challenging to target extrahepatic tissues in a flexible and image-guided manner. To address this issue, we report a bioorthogonal pre-targeting strategy that uses focused ultrasound to promote the delivery of mRNA-loaded lipid nanoparticles (mRNA-LNP). We synthesized amphiphilic click reactive anchors (ACRAs) consisting of a phospholipid PEG-conjugate functionalized with transcyclooctene (TCO) or its companion reactive partner methyltetrazine (mTz), yielding ACRA-TCO and ACRA-mTz.

Amplifying mutational profiling of extracellular vesicle mRNA with SCOPE.

Sequencing of messenger RNA (mRNA) found in extracellular vesicles (EVs) in liquid biopsies can provide clinical information such as somatic mutations, resistance profiles and tumor recurrence. Despite this, EV mRNA remains underused due to its low abundance in liquid biopsies, and large sample volumes or specialized techniques for analysis are required. Here we introduce Self-amplified and CRISPR-aided Operation to Profile EVs (SCOPE), a platform for EV mRNA detection.

Chondroitin sulfate-based microneedles for transdermal delivery of stem cell-derived extracellular vesicles to treat rheumatoid arthritis.

For the non-invasive treatment of rheumatoid arthritis (RA), a chondroitin sulfate C (CSC)-based dissolving microneedles (cMN) was prepared to deliver human adipose stem cell-derived extracellular vesicles (hASC-EV) into inflamed joints. Owing to their anti-inflammatory function, the hASC-EV-bearing cMN (EV@cMN) significantly suppressed activated fibroblast-like synoviocytes (aFLS) and M1 macrophages (M1), which are responsible for the progression of RA. In addition, EV@cMN facilitated the chondrogenic differentiation of bone marrow-derived stem cells.

Functionally Masked Antibody to Uncouple Immune-Related Toxicities in Checkpoint Blockade Cancer Therapy.

Of the existing immunotherapy drugs in oncology, monoclonal antibodies targeting the immune checkpoint axis are preferred because of the durable responses observed in selected patients. However, the associated immune-related adverse events (irAEs), causing uncommon fatal events, often require specialized management and medication discontinuation. The study aim was to investigate our hypothesis that masking checkpoint antibodies with tumor microenvironment (TME)-responsive polymer chains can mitigate irAEs and selectively target tumors by limiting systemic exposure to patients.

Cascade-amplified self-immolative polymeric prodrug for cancer therapy by disrupting redox homeostasis.

The amplification of reactive oxygen species (ROS) generation and glutathione (GSH) depletion in cancer cells represents a promising strategy to disrupt redox homeostasis for cancer therapy. Quinone methide and its analogs (QM) have recently been recognized as potential GSH scavengers for anticancer applications; however, an effective QM prodrug is yet to be developed. In this study, we prepare a self-immolative polymeric prodrug (SPP), which could be selectively degraded to generate large quantities of QMs in cancer cells during the spontaneous stepwise head-to-tail degradation of SPP.

Self-immolative polymer-based immunogenic cell death inducer for regulation of redox homeostasis.

Doxorubicin (DOX), widely used as an anticancer drug, is considered an immunogenic cell death (ICD) inducer that enhances cancer immunotherapy. However, its extended application as an ICD inducer has been limited owing to poor antigenicity and inefficient adjuvanticity. To enhance the immunogenicity of DOX, we prepare a reactive oxygen species (ROS)-responsive self-immolative polymer (R-SIP) that can efficiently destroy redox homeostasis via self-immolation-mediated glutathione depletion in cancer cells.

Chemiluminescence resonance energy transfer-based immunostimulatory nanoparticles for sonoimmunotherapy.

Sonodynamic therapy (SDT) has recently emerged as a promising alternative to photodynamic therapy because of its applicability in treating deeply located tumors accessible by ultrasound (US). However, the therapeutic potential of conventional sonosensitizers is limited by the low quantum yield of reactive oxygen species (ROS) and poor immune responses eliciting canonical apoptosis of cancer cells. Herein, we report chemiluminescence resonance energy transfer (CRET)-based immunostimulatory nanoparticles (iCRET NPs) for sonoimmunotherapy, which not only amplify the ROS quantum yield of sonosensitizers but also generate carbon dioxide (CO) bubbles to induce immunogenic cell death in the tumor microenvironment (TME).

Stem Cell-Derived Extracellular Vesicle-Bearing Dermal Filler Ameliorates the Dermis Microenvironment by Supporting CD301b-Expressing Macrophages.

Hyaluronic acid-based hydrogels (Hyal-Gels) have the potential to reduce wrinkles by physically volumizing the skin. However, they have limited ability to stimulate collagen generation, thus warranting repeated treatments to maintain their volumizing effect. In this study, stem cell-derived extracellular vesicle (EV)-bearing Hyal-Gels (EVHyal-Gels) were prepared as a potential dermal filler, ameliorating the dermis microenvironment.

Gold-installed hyaluronic acid hydrogel for ultrasound-triggered thermal elevation and on-demand cargo release.

The temporal and quantitative control of the cargo release is a challenging issue in the application of hydrogels for cancer therapy. Here, we report hyaluronic acid hydrogel-based depot that provides ultrasound-triggered thermal elevation and on-demand cargo release. The hyaluronic acid hydrogel was developed by employing the gold cluster as a sonothermal crosslinker which was grown on the cargo to prevent its undesired leakage until ultrasound-induced dissociation.

An anti-DR5 antibody-curcumin conjugate for the enhanced clearance of activated hepatic stellate cells.

Anti-death receptor 5 (DR5) antibody is a potential therapeutic agent for liver fibrosis because it exhibits anti-fibrotic effects by inducing the apoptosis of activated hepatic stellate cells (HSCs), which are responsible for hepatic fibrogenesis. However, the clinical applications of anti-DR5 antibodies have been limited by their low agonistic activity against DR5. In this study, an anti-DR5 antibody-curcumin conjugate (DCC) was prepared to investigate its effect on the clearance of activated HSCs.

Vitamin A-coupled stem cell-derived extracellular vesicles regulate the fibrotic cascade by targeting activated hepatic stellate cells in vivo.

Allogeneic transplantation of mesenchymal stem cell-derived extracellular vesicles (EVs) offers great potential for treating liver fibrosis. However, owing to their intrinsic surface characteristics, bare EVs are non-specifically distributed in the liver tissue after systemic administration, leading to limited therapeutic efficacy. To target activated hepatic stellate cells (HSCs), which are responsible for hepatic fibrogenesis, vitamin A-coupled small EVs (V-EVs) were prepared by incorporating vitamin A derivative into the membrane of bare EVs.

Psammocindoles A-C: Isolation, Synthesis, and Bioactivity of Indole-γ-lactams from the Sponge .

Psammocindoles A-C (-), a new class of indole alkaloids, were isolated from a sponge. By combined spectroscopic analyses, the structures of these compounds were determined to be the indole-γ-lactams derived from three amino acid residues. In addition, an enantiomer psammocindole D (), and the -lactam isomers isopsammocindoles A-D (-) were also synthesized.

Cavitation-Inducible Mesoporous Silica-Titania Nanoparticles for Cancer Sonotheranostics.

Sonodynamic therapy has received increasing attention for cancer treatments as an alternative to photodynamic therapy. However, its clinical applications have been limited by the lack of a sonosensitizer that is capable of producing sufficient amounts of reactive oxygen species (ROS) in response to ultrasound (US) exposure. Herein, PEGylated mesoporous silica-titania nanoparticles (P-MSTNs) are prepared and used as US-responsive nanocarriers for cancer sonotheranostics.

Chemiluminescence resonance energy transfer-based nanoparticles for quantum yield-enhanced cancer phototheranostics.

Chemiluminescence (CL) has recently gained attention for CL resonance energy transfer (CRET)-mediated photodynamic therapy of cancer. However, the short duration of the CL signal and low quantum yield of the photosensitizer have limited its translational applications. Here, we report CRET-based nanoparticles (CRET-NPs) to achieve quantum yield-enhanced cancer phototheranostics by reinterpreting the hidden nature of CRET.

Hypoxia-responsive nanoparticles for tumor-targeted drug delivery.

Hypoxia is a negative prognostic indicator of solid tumors. Increasing evidence indicates that the intratumoral hypoxic microenvironment is strongly related to enhanced tumor aggressiveness, decreased therapeutic effect and poor prognosis of chemotherapy, radiotherapy (RT), and photodynamic therapy (PDT). However, due to an unusual gene expression profile and abnormal metabolism, enzymes responsible for reduction reactions or electron donation are highly reactive in hypoxic tumor cells and provide the possibility of exploiting targeted drug delivery systems for cancer therapy.

Hypoxia-Responsive Mesoporous Nanoparticles for Doxorubicin Delivery.

Hypoxia, or low oxygen tension, is a common feature of solid tumors. Here, we report hypoxia-responsive mesoporous silica nanoparticles (HR-MSNs) with a 4-nitroimidazole-β-cyclodextrin (NI-CD) complex that is acting as the hypoxia-responsive gatekeeper. When these CD-HR-MSNs encountered a hypoxic environment, the nitroimidazole (NI) gatekeeper portion of CD-HR-MSNs disintegrated through bioreduction of the hydrophobic NI state to the hydrophilic NI state.

Ultrasmall gold nanosatellite-bearing transformable hybrid nanoparticles for deep tumor penetration.

Unlabelled: Since delivering drugs to an entire tumoral region leads to high therapeutic efficacy and good prognosis, achieving deep tumoral penetration of drugs is a major issue in cancer treatment. In this regard, conventional nanomedicines (>50 nm) have shown limitations in cancer therapy, primarily attributed to the heterogeneous distribution of drugs because of the physiological barrier of the tumor interstitial space. To address this issue, we prepared transformable hybrid nanoparticles (TNPs) consisting of a pH-responsive nanocarrier (PEG-PBAE) and doxorubicin (DOX)-conjugated ultrasmall (<3 nm) gold nanoparticles (nanosatellites).

Carboxymethyl dextran-based hypoxia-responsive nanoparticles for doxorubicin delivery.

In an attempt to develop the hypoxia-responsive nanoparticles for cancer therapy, a polymer conjugate, consisting of carboxymethyl dextran (CMD) and black hole quencher 3 (BHQ3), was prepared. The polymer conjugate can self-assemble into nanoparticles (CMD-BHQ3 NPs) under aqueous conditions. The anticancer drug, doxorubicin (DOX), was loaded in CMD-BHQ3 NPs to prepare DOX@CMD-BHQ3 NPs.

Anti-Trop2 antibody-conjugated bioreducible nanoparticles for targeted triple negative breast cancer therapy.

Trop2, a transmembrane glycoprotein, has emerged as a biomarker for targeted cancer therapy since it is overexpressed in 80% of triple negative breast cancer (TNBC) patients. For the site-specific delivery of the anticancer drug into TNBC, anti-Trop2 antibody-conjugated nanoparticles (ST-NPs) were prepared as the potential nanocarrier, composed of carboxymethyl dextran (CMD) derivatives with bioreducible disulfide bonds. Owing to its amphiphilicity, the CMD derivatives were self-assembled into nano-sized particles in an aqueous condition.

Gold-stabilized carboxymethyl dextran nanoparticles for image-guided photodynamic therapy of cancer.

Photodynamic therapy (PDT) has been extensively investigated to treat cancer since it induces cell death through the activation of photosensitizers by light. However, its success has been hampered by the insufficient selectivity of photosensitizers to tumor tissues. In an attempt to increase the therapeutic efficacy of PDT by targeting the photosensitizer specifically to the tumor site, we prepared chlorin e6 (Ce6)-loaded gold-stabilized carboxymethyl dextran nanoparticles (Ce6-GS-CNPs).

Anti-Melanogenic Activity of Gagunin D, a Highly Oxygenated Diterpenoid from the Marine Sponge Phorbas sp., via Modulating Tyrosinase Expression and Degradation.

Tyrosinase is the rate-limiting enzyme critical for melanin synthesis and controls pigmentation in the skin. The inhibition of tyrosinase is currently the most common approach for the development of skin-whitening cosmetics. Gagunin D (GD), a highly oxygenated diterpenoid isolated from the marine sponge sp.

Improvement of Antitumor Efficacy by Combination of Thermosensitive Liposome with High-Intensity Focused Ultrasound.

High intensity focused ultrasound (HIFU), allowing for precise heating of the deep and local area, is emerging as the source of mild hyperthermia for delivery of doxorubicin (DOX) using thermosensitive liposomes (TSLs). Conventionally, HIFU has been used for intravascular drug release at tumor tissue by inducing mild hyperthermia immediately upon systemic administration of DOX-TSLs. This immediate heating approach (IHA), however, limits the deep penetration of DOX for high anticancer efficacy.

Tumor microenvironment-specific nanoparticles activatable by stepwise transformation.

In an attempt to develop the tumor-targeted nanocarrier which can surmount major challenges for in vivo application, we prepared tumor microenvironment-specific nanoparticles which can be sequentially activated at the extracellular and intracellular levels of tumor tissue by stepwise transformation. This polymeric nanoparticle has been prepared using an amphiphilic polyethyleneimine derivative with the pH-responsive charge-convertible moiety and the reduction-responsive crosslink. Once reaching the tumor tissue in vivo after systemic administration, the surface charge of this nanoparticle can be converted from negative to positive by recognizing the mildly acidic extracellular matrix of tumor, allowing for the enhanced cellular uptake.

Gold-installed biostable nanocomplexes for tumor-targeted siRNA delivery in vivo.

The key issues, associated with nanocarriers for small interfering RNAs (siRNAs), are their poor stability and lack of tumor targetability in vivo. To address these issues, we developed gold-installed polyethyleneimine/siRNA complexes with a corona of PEGylated hyaluronic acid.