Chitosan-based food-grade Pickering emulsion loading with Rosa roxburghii extract against precancerous lesions of gastric carcinoma.

Precancerous lesions of gastric carcinoma (PLGC) are the most important stage in the development of gastric cancer, accompanied by significant oxidative stress and inflammatory response. Rosa roxburghii extract (RRE) has unique advantages in anti-PLGC due to its multi-component, high antioxidant and anti-inflammatory activities. However, the astringency and instability of RRE in the digestive tract seriously hinder its clinical application. Herein, we report a chitosan-based food-grade Pickering emulsion (PE) for loading RRE to block unpleasant taste, improve stability, and promote the entry of RRE into gastric epithelial cells through the gastric adhesion of chitosan, thereby enhancing preventive and therapeutic effects against PLGC. This Pickering emulsion is constructed as a water-in-oil (W/O) emulsion stabilized by the food-grade nanoparticles composed of soybean protein isolate (SPI) and chitosan (CS) through electrostatic interaction (defined as RRE@PE). The experimental results showed that RRE@PE performed better efficacy against PLGC than RRE by scavenging or inhibiting reactive oxygen species generation and reducing inflammatory cytokines. This Pickering emulsion enhances the application potential of RRE and is expected to be used for the treatment of clinical patients with PLGC.

Size-exclusion chromatography-based extracellular vesicle size subtyping and multiplex membrane protein profiling for differentiating gastrointestinal cancer prognosis.

Extracellular vesicles (EVs), as a type of subcellular structure, have been extensively researched for their potential for developing advanced diagnostic technologies for various diseases. However, the biomolecular and biophysical heterogeneity of EVs has restricted their application in clinical settings. In this article, we developed a size-exclusion chromatography-based technique for simultaneous EV size subtyping and protein profiling. By eluting fluorescent aptamer-treated patient plasma through a size-exclusion column, the mixture can be classified into 50 nm aptamer-bound EVs, 100 nm aptamer-bound EVs and free-floating aptamers, which could further enable multiplex EV membrane protein profiling by analyzing the fluorescence intensities of EV-bound aptamers. Using this technique, we successfully identified EV size subtypes for differentiating gastrointestinal cancer prognosis states. Overall, we developed a rapid, user-friendly and low-cost EV size subtyping and protein profiling technique, which holds great potential for identifying crucial EV size subtypes for disease diagnosis in the clinic.

Dual-Ligand Synergistic Targeting Anti-Tumor Nanoplatforms with Cascade-Responsive Drug Release.

Dual-ligand targeting drug delivery nanoplatforms are considered a promising tool for enhancing the specificity of chemotherapy. However, serious off-target delivery has been observed in current dual-ligand targeting nanoplatforms, as each ligand can independently recognize receptors on the cell membrane surface and guide drug nanocarriers to different cells. To overcome this barrier, a dual-ligand synergistic targeting (DLST) nanoplatform is developed, which can guide chemotherapy treatment specifically to cancer cells simultaneously overexpressing two receptors. This nanoplatform consists of a singlet oxygen (1O2) photosensitizer-loaded nanocarrier and a drug-loaded nanocarrier with 1O2 responsiveness, which were, respectively, decorated with a pair of complementary DNA sequences and two different ligands. For cancer cells overexpressing both receptors, two nanocarriers can be internalized in larger quantities to cause DNA hybridization-induced nanocarrier aggregation, which further activates 1O2-triggered drug release under light irradiation. For cells overexpressing a single receptor, only one type of nanocarrier can be internalized in a large quantity, leading to blocked drug release due to the ultrashort action radius of 1O2. In vivo evaluation showed this DLST nanoplatform displayed highly specific tumor treatment with minimized long-term toxicity. This is a highly efficient drug delivery system for DLST chemotherapy, holding great potential for clinical applications.

Utilizing endosomal capture for tumor therapy via membrane-lytic mechanism-based Pickering emulsion.

Nanocarriers are easily captured by endosomes, where the abundant hydrolases inevitably destroy the nanocarriers and the drugs they carry, ultimately resulting in a compromised or lost therapeutic efficacy. Herein, we report a membrane-lytic mechanism-based Pickering emulsion that can in turn utilize this seemingly unfavorable endosomal capture behavior for tumor therapy. This Pickering emulsion is constructed as an oil-in-water (O/W) emulsion stabilized by the hybrid nanoparticles (HNPs) composed of two molecules with opposite charges, cetyl trimethylamine bromide (CTAB) and linoleic acid (LA), through electrostatic interaction (defined as HNPs@PE). After HNPs@PE enters the lysosomes through macropinocytosis-mediated endocytosis, LA can be protonated in response to the acidic stimulus, and causing the swelling or disintegration of HNPs due to the disrupted electrostatic interaction. The released CTAB holds strong membrane-lytic activity and can directly damage the lysosomal membranes. Under the acidic condition and the participation of excessive iron ions (II) in lysosomes, LA induces lipid peroxidation and the resulting lipid peroxides (LPO) will oxidize the lysosomal membranes, collectively causing the leakage of lysosome membranes and the release of contents into cytoplasm. Subsequently, the diffused CTAB and LPO will continue to attack the mitochondrial membranes and cell membranes, resulting in the death of different types of tumor cells both in vitro and in vivo due to membrane damage. This Pickering emulsion with membrane-lytic ability represents a potential self-anticancer nanocarrier.

Boosting ROS-Mediated Lysosomal Membrane Permeabilization for Cancer Ferroptosis Therapy.

Due to the deficient catalase, abundant reduced iron and low acidic environment in lysosomes, inducing lysosomal membrane permeabilization (LMP) through Fenton reaction-based reactive oxygen species (ROS) generation recently attracts increasing attention in cancer therapy. However, the lysosomal membranes are protected by highly glycosylated membrane proteins and several endolysosomal damage-response mechanisms can rapidly repair the injured lysosomes. To produce sufficient ROS and cause complete lysosomal membranes rupture, a lysosome-targeted ROS inducer, N-(3-Aminopropyl) morpholine grafted cross-linked lipoic acid vesicles with vitamin C-loading (VC@N3AM cLAVs), is developed. VC@N3AM cLAVs efficiently accumulate in lysosomes and convert into two redox couples LA/DHLA (dihydrolipoic acid, reduced form of LA) and VC/DHA (dehydroascorbic acid, oxidized form of VC) by the lysosomal glutathione, which can not only produce a large amount of H2 O2 by pro-oxidant action but also accelerate iron transformation through the cyclic redox reactions between each other and cause the efficient conversion of the generated H2 O2 into highly toxic •OH. Both in vitro and in vivo experiments demonstrate that VC@N3AM cLAVs can effectively enhance ROS production and boost LMP, finally initiation irreversible death of tumor cells via ferroptosis pathway, thus representing a potential anticancer drug for cancer therapy.

A hydrogel-based mechanical metamaterial for the interferometric profiling of extracellular vesicles in patient samples.

The utility of mechanical metamaterials for biomedical applications has seldom been explored. Here we show that a metamaterial that is mechanically responsive to antibody-mediated biorecognition can serve as an optical interferometric mask to molecularly profile extracellular vesicles in ascites fluid from patients with cancer. The metamaterial consists of a hydrogel responsive to temperature and redox activity functionalized with antibodies to surface biomarkers on extracellular vesicles, and is patterned into micrometric squares on a gold-coated glass substrate. Through plasmonic heating, the metamaterial is maintained in a transition state between a relaxed form and a buckled state. Binding of extracellular vesicles from the patient samples to the antibodies on the hydrogel causes it to undergo crosslinking, induced by free radicals generated via the activity of horseradish peroxidase conjugated to the antibodies. Hydrogel crosslinking causes the metamaterial to undergo fast chiral re-organization, inducing amplified changes in its mechanical deformation and diffraction patterns, which are detectable by a smartphone camera. The mechanical metamaterial may find broad utility in the sensitive optical immunodetection of biomolecules.

Cyclodextrin-Based Nanoplatforms for Tumor Phototherapy: An Update.

Tumor phototherapies are light-mediated tumor treatment modalities, which usually refer to tumor photothermal therapy (PTT) and photodynamic therapy (PDT). Due to the outstanding spatial-temporal control over treatment through light irradiation, tumor phototherapies display extremely low side effects during treatment and are believed to be a tumor treatment method with a clinical translation potential. However, current tumor phototherapy nanoplatforms face obstacles, including light irradiation-induced skin burning, tumor hypoxia microenvironments, limited light penetration depth, et al. Therefore, one important research direction is developing a tumor phototherapy nanoplatform with multifunctionality and enhanced pharmacological effects to overcome the complexity of tumor treatment. On the other hand, cyclodextrins (CDs) are starch-originated circular oligosaccharides with negligible toxicity and have been used to form supermolecular nanostructures through a host-guest interaction between the inner cavity of CDs and functional biomolecules. In the past few years, numerous studies have focused on CD-based multifunctional tumor phototherapy nanoplatforms with an enhanced photoeffect, responsive morphological transformation, and elevated drug bioavailability. This review focuses on the preparation methods of CD-based tumor phototherapy nanoplatforms and their unique physiochemical properties for improving anti-tumor pharmacological efficacy.

Polymeric photothermal agents for cancer therapy: recent progress and clinical potential.

Over the past decades, near infrared light (NIR)-sensitive photothermal agents (PTAs) that can efficiently absorb light and generate heat have been investigated worldwide for cancer photothermal therapy (PTT) and the combination treatments, which have some peculiar advantages including spatiotemporal targeting, the ability-to-reverse multidrug resistance, the immunity-stimulating function, and the synergistic effect in combination treatments. In this review, we first focus on emerging melanin-like polymers and coordination polyphenol polymer-based PTAs that hold transition potential because of their facile synthesis and good biocompatibility/biodegradability. We briefly introduce polymeric PTAs for emerging NIR-II (1000-1700 nm) PTT in deep tumors to overcome shallow penetration depth and threshold irradiation intensity of NIR-I (700-900 nm). Then we discuss polymeric PTAs for combination PTT treatments with photodynamic therapy (PDT), ferroptosis therapy (ferrotherapy), and immunotherapy, which are intensively studied for achieving anticancer synergistic effects. Finally, we discuss those polymeric PTAs for reversing cancer multidrug resistance and for mild/low-temperature PTT (43 °C ≤ T < 50 °C) in contrast to conventional high-temperature PTT (>50 °C). The polymeric PTA-based PTT and the combination treatments are still being developed in the early stage and need much more effort before potential clinical transitions and applications.

Plasmonic, Targeted, and Dual Drugs-Loaded Polypeptide Composite Nanoparticles for Synergistic Cocktail Chemotherapy with Photothermal Therapy.

To integrate cocktail chemotherapy with photothermal therapy into one biocompatible and biodegradable nanocarrier, the plasmonic, lactose-targeted, and dual anticancer drugs-loaded polypeptide composite nanoparticles were for the first time fabricated under mild conditions. The glyco-PEGylated polypeptide micelles that self-assembled from the lactose (LAC) and PEG grafted polycysteine terpolymer were used as templates to generate the plasmonic composite nanoparticles, as mainly characterized by DLS, TEM, SEM, and XPS. These composite nanoparticles showed a broad and strong near-infrared (NIR) absorption at 650-1100 nm and increased the temperature of phosphate buffer solution by 30.1 °C upon a continuous-wave laser irradiation (808 nm, 5 min, 2 W·cm(-2)), while the same dose of NIR-mediated heating completely killed HepG2 cancer cells in vitro, presenting excellent photothermal properties. Two anticancer drugs, doxorubicin (DOX) and 6-mercaptopurine (6-MP), were loaded into the composite nanoparticles through physical interactions and Au-S bond, respectively. The dual drugs-loaded composite nanoparticles exhibited reduction-sensitive and NIR-triggered cocktail drugs release profiles and trigger-enhanced cytotoxicity. As evidenced by flow cytometry, fluorescence microscopy, and MTT assay, the LAC-coated composite nanoparticles were more internalized by the HepG2 than the HeLa cell line, demonstrating a LAC-targeting enhanced cytotoxicity toward HepG2. The combination cocktail chemo-photothermal therapy produced a lower half maximal inhibitory concentration than cocktail chemotherapy or photothermal therapy alone, displaying a good synergistic antitumor effect.

An autoreduction method to prepare plasmonic gold-embedded polypeptide micelles for synergistic chemo-photothermal therapy.

Biodegradable, biocompatible polypeptide micelles were used as a reducing agent and template in an autoreduction method for preparing plasmonic gold-embedded polypeptide micelles under mild conditions. The micelles were fully characterized by DLS, TEM, SEM, and AFM. The in situ reduced gold was embedded in the interior core of the disulfide bond-cross-linked polypeptide micelles by forming multivalent Au-S bonds. The plasmonic gold-embedded micelles showed strong near-infrared (NIR) light absorption and NIR-mediated photothermal properties including high photothermal conversion efficiency and good photostability. After continuous-wave diode laser irradiation for 5 min (808 nm, 2 W cm-2), the NIR light-induced heating of the gold-embedded micelles efficiently killed cancer cells in vitro, as observed by a double fluorescent staining technique. A standard MTT assay, flow cytometry, and fluorescence microscopy showed that the anticancer drug doxorubicin (DOX)-loaded and gold-embedded micelles quickly entered HeLa cells and gave a lower half-maximal inhibitory concentration (IC50) than for chemotherapy or photothermal therapy alone, demonstrating a good synergistic effect for the combination chemo-photothermal therapy. Consequently, this work provides a versatile strategy for fabricating plasmonic polypeptide composite nanoparticles, which are promising for synergistic chemo-photothermal cancer therapy.

A sweet polydopamine nanoplatform for synergistic combination of targeted chemo-photothermal therapy.

Inspired by sweet or sugar-coated bullets that are used for medications in clinics and the structure and function of biological melanin, a novel kind of sweet polydopamine nanoparticles and their anticancer drug doxorubicin loaded counterparts are prepared, which integrate an active targeting function, photothermal therapy, and chemotherapy into one polymeric nanocarrier. The oxidative polymerization of lactosylated dopamine and/or with dopamine are performed under mild conditions and the resulting sweet nanoparticles are thoroughly characterized. When exposed to an 808 nm continuous-wave diode laser, the magnitude of temperature elevation not only increases with the concentration of nanoparticles, but can also be tuned by the laser power density. The nanoparticles possess strong near infrared light absorption, high photothermal conversion efficiency, and good photostability. The nanoparticles present tunable binding with RCA120 lectin and a targeting effect to HepG2 cells, confirmed by dynamic light scattering, turbidity analysis, MTT assay, and flow cytometry. Importantly, the sweet nanoparticles give the lowest IC50 value of 11.67 µg mL(-1) for chemo-photothermal therapy compared with 43.19 µg mL(-1) for single chemotherapy and 67.38 µg mL(-1) for photothermal therapy alone, demonstrating a good synergistic effect for the combination therapy.