Rational construction of CQDs-based targeted multifunctional nanoplatform for synergistic chemo-photothermal tumor therapy.

Photothermal therapy combined with chemotherapy has shown great promise in the treatment of cancer. In this synergistic system, a safe, stable, and efficient photothermal agent is desired. Herein, an effective photothermal agent, carbon quantum dots (CQDs), was initially synthesized and then rationally constructed a folic acid (FA)-targeted photothermal multifunctional nanoplatform by encapsulating CQDs and the anticancer drug doxorubicin (DOX) in the liposomes. Indocyanine green (ICG), a near infrared (NIR) photothermal agent, approved by the U.S. Food and Drug Administration, was embedded in the bilayer membrane to further enhance the photothermal effects and facilitate the rapid cleavage of liposomes for drug release. Triggered by the NIR laser, this engineered photothermal multifunctional nanoplatform, not only exhibited an excellent performance with the photothermal conversion efficiency of up to 47.14%, but also achieved controlled release of the payloads. In vitro, and in vivo experiments demonstrated that the photothermal multifunctional nanoplatform had excellent biocompatibility, enhanced tumor-specific targeting, stimuli-responsive drug release, effective cancer cell killing and tumor suppression through multi-modal synergistic therapy. The successful construction of this NIR light-triggered targeted photothermal multifunctional nanoplatform will provide a promising strategy for the design and development of synergistic chemo-photothermal combination therapy and improve the therapeutic efficacy of cancer treatment.

Recent advances in nanocrystal-based technologies applied for ocular drug delivery.

INTRODUCTION: The intricate physiological barriers of the eye and the limited volume of eye drops impede efficient delivery of poorly water-soluble drugs. In the last decade, nanocrystals have emerged as versatile drug delivery systems in various administration routes from bench to bedside. The unique superiorities of nanocrystals, mainly embodied in high drug-loading capacity, good mucosal adhesion and penetration, and greatly improved drug solubility, reveal a promising prospect for ocular delivery of poorly water-soluble drugs. AREAS COVERED: This article focuses on the ophthalmic nanocrystal technologies and products that are in the literature, clinical trials, and even on the market. The recent research progress in the preparation, ocular application, and absorption of nanocrystals are highlighted, and the pros and cons of nanocrystals in overcoming the physiological barriers of the eye are also summarized. EXPERT OPINION: Nanocrystals have demonstrated success as glucocorticoid eye drops in the treatment of anterior segment diseases. However, the thermodynamic stability of nanocrystals remains the major challenge in product development. New technologies for efficiently optimizing stabilizers and sterilization processes are still expected. Strategies to confer more diverse functions via surface modification are also worth exploration to improve the potential of nanocrystals in delivering poorly water-soluble drugs to posterior segment of the eye.

Intranasal G5-BGG/pDNA Vaccine Elicits Protective Systemic and Mucosal Immunity against SARS-CoV-2 by Transfecting Mucosal Dendritic Cells.

Infectious disease pandemics, including the coronavirus disease 2019 pandemic, have heightened the demand for vaccines. Although parenteral vaccines induce robust systemic immunity, their effectiveness in respiratory mucosae is limited. Considering the crucial role of nasal-associated lymphoid tissue (NALT) in mucosal immune responses, in this study, the intranasal complex composed of G5-BGG and antigen-expressing plasmid DNA (pSP), named G5-BGG/pSP complex, is developed to activate NALT and to promote both systemic and mucosal immune defense. G5-BGG/pSP could traverse mucosal barriers and deliver DNA to the target cells because of its superior nasal retention and permeability characteristics. The intranasal G5-BGG/pSP complex elicits robust antigen-specific immune responses, such as the notable production of IgG antibody against several virus variants. More importantly, it induces elevated levels of antigen-specific IgA antibody and a significant expansion of the lung-resident T lymphocyte population. Notably, the intranasal G5-BGG/pSP complex results in antigen expression and maturation of dendritic cells in nasal mucosae. These findings exhibit the potential of G5-BGG, a novel cationic material, as an effective gene carrier for intranasal vaccines to obtain robust systemic and mucosal immunity.

Ocular therapies with biomacromolecules: From local injection to eyedrop and emerging noninvasive delivery strategies.

The last two decades have witnessed a continuously increasing number of biomacromolecules approved for the treatment of ocular diseases. The eye possesses multiple protective mechanisms to resist the invasion of exogenous substances, but meanwhile these physiological defense systems also act as strong barriers, impeding absorption of most biomacromolecules into the eye. As a result, local injections play predominant roles for posterior ocular delivery of biomacromolecules in clinical practice. To achieve safe and convenient application of biomacromolecules, alternative strategies to realize noninvasive intraocular delivery are necessary. Various nanocarriers, novel penetration enhancers and physical strategies have been explored to facilitate delivery of biomacromolecules to both anterior and posterior ocular segments but still suffered difficulties in clinical translation. This review compares the anatomical and physiological characteristics of the eyes from those frequently adopted experimental species and profiles the well-established animal models of ocular diseases. We also summarize the ophthalmic biomacromolecules launched on the market and put emphasis on emerging noninvasive intraocular delivery strategies of peptides, proteins and genes.

Intraocular siRNA Delivery Mediated by Penetratin Derivative to Silence Orthotopic Retinoblastoma Gene.

Gene therapy brings a ray of hope for inherited ocular diseases that may cause severe vision loss and even blindness. However, due to the dynamic and static absorption barriers, it is challenging to deliver genes to the posterior segment of the eye by topical instillation. To circumvent this limitation, we developed a penetratin derivative (89WP)-modified polyamidoamine polyplex to deliver small interference RNA (siRNA) via eye drops to achieve effective gene silencing in orthotopic retinoblastoma. The polyplex could be spontaneously assembled through electrostatic and hydrophobic interactions, as demonstrated by isothermal titration calorimetry, and enter cells intactly. In vitro cellular internalization revealed that the polyplex possessed higher permeability and safety than the lipoplex composed of commercial cationic liposomes. After the polyplex was instilled in the conjunctival sac of the mice, the distribution of siRNA in the fundus oculi was significantly increased, and the bioluminescence from orthotopic retinoblastoma was effectively inhibited. In this work, an evolved cell-penetrating peptide was employed to modify the siRNA vector in a simple and effective way, and the formed polyplex interfered with intraocular protein expression successfully via noninvasive administration, which showed a promising prospect for gene therapy for inherited ocular diseases.

Influence of lung cancer model characteristics on tumor targeting behavior of nanodrugs.

Evidence is mounting that there is a significant gap between the antitumor efficacy of nanodrugs in preclinical mouse tumor models and in clinical human tumors, and that differences in tumor models are likely to be responsible for this gap. Herein, we investigated the enhanced permeability and retention (EPR) effect in mouse lung cancer models with different tumor growth rates, volumes and locations, and analyzed the nanodrug tumor targeting behaviors limited by tumor vascular pathophysiological characteristics in various tumor models. The results showed that the fast-growing tumors were characterized by lower vascular tight junctions, leading to higher vascular paracellular transport activity and nanodrug tumor accumulation. The paracellular transport activity increased with the growth of tumor, but the vascular density and transcellular transport activity decreased, and as a result, the average tumor accumulation of passive targeting nanodrugs decreased. Orthotopic tumors were rich in blood vessels, but had low vascular transcellular and paracellular transport activities, making it difficult for nanodrug accumulation in orthotopic tumors via passive targeting strategies. The antitumor efficacy of passive targeting nanodrugs in various lung cancer-bearing mice validated the aforementioned nanodrug accumulation behavior, and nanodrugs based on the angiogenesis-tumor sequential targeting strategy achieved obviously improved efficacy in orthotopic lung cancer-bearing mice. These results suggest that the EPR effect varies in different tumor models and should not be used as a universal targeting strategy for antitumor nanodrugs. Besides, attention should be paid to the animal tumor models in the evaluation of nanodrugs so as to avoid exaggerating the antitumor efficacy.

Experimental demonstration of separating the wave‒particle duality of a single photon with the quantum Cheshire cat.

As a fundamental characteristic of physical entities, wave‒particle duality describes whether a microscopic entity exhibits wave or particle attributes depending on the specific experimental setup. This assumption is premised on the notion that physical properties are inseparable from the objective carrier. However, after the concept of the quantum Cheshire cats was proposed, which makes the separation of physical attributes from the entity possible, the premise no longer holds. Furthermore, an experimental demonstration of the separation of the wave and particle attributes inspired by this scenario remains scarce. In this work, we experimentally separated the wave and particle attributes of a single photon by exploiting the quantum Cheshire cat concept for the first time. By applying a weak disturbance to the evolution of the system, we achieve an effect similar to the quantum Cheshire cat and demonstrated the separation of the wave and particle attributes via the extraction of weak values. Our work provides a new perspective for the in-depth understanding of wave‒particle duality and promotes the application of weak measurements in fundamentals of quantum mechanics.

The two-component response regulator OrrA confers dehydration tolerance by regulating avaKa expression in the cyanobacterium Anabaena sp. strain PCC 7120.

The cyanobacterium Anabaena sp. strain PCC 7120 exhibits dehydration tolerance. The regulation of gene expression in response to dehydration is crucial for the acquisition of dehydration tolerance, but the molecular mechanisms underlying dehydration responses remain unknown. In this study, the functions of the response regulator OrrA in the regulation of salt and dehydration responses were investigated. Disruption of orrA abolished or diminished the induction of hundreds of genes in response to salt stress and dehydration. Thus, OrrA is a principal regulator of both stress responses. In particular, OrrA plays a crucial role in dehydration tolerance because an orrA disruptant completely lost the ability to regrow after dehydration. Moreover, in the OrrA regulon, avaKa encoding a protein of unknown function was revealed to be indispensable for dehydration tolerance. OrrA and AvaK are conserved among the terrestrial cyanobacteria, suggesting their conserved functions in dehydration tolerance in cyanobacteria.

Topical instillation of cell-penetrating peptide-conjugated melphalan blocks metastases of retinoblastoma.

Retinoblastoma is the most common primary intraocular malignancy in infancy with a metastases-related death risk. However, a safe and convenient treatment without enucleation is still an unmet clinical need. In this work, a cell-penetrating peptide, 89WP, was conjugated with melphalan (89WP-Mel), which achieved high tumor inhibition effects as intravitreally injected melphalan via topical instillation for the first time. Notably, the "outside-in" diffusion of instilled 89WP-Mel created a protective shield surrounding the eye, efficiently preventing tumor metastases, while the mice treated with intravitreally injected melphalan suffered more brain metastases related death. The ocular absorption of 89WP-conjugated melphalan and other small molecules, both hydrophobic and hydrophilic, occurred via non-corneal pathway with high safety and a prolonged residence duration in retina up to 24 h. The present work paves a new avenue for simultaneous intraocular tumor inhibition and extraocular metastases prevention in a safe and convenient way via topical instillation.

Core-shell lipoplexes inducing active macropinocytosis promote intranasal delivery of c-Myc siRNA for treatment of glioblastoma.

Glioblastoma is the most common and aggressive primary brain tumor, whose malignancy is closely correlated with elevated proto-oncogene c-myc. Intranasal administration emerges as a potential approach to deliver gene into the brain and interfere c-Myc expression. However, powerful permeability in nasal mucosa, selective delivery to glioma and avoidance of premature release during remote transport are imperative to ensure the therapeutic effectiveness. To address the above concerns, herein we constructed a lipoplex based on pre-compression of c-Myc-targeting siRNA (sic-Myc) by octaarginine and subsequent encapsulation by liposome modified with a selected peptide derived from penetratin, named 89WP. It was found that the lipoplex exhibited a stable core-shell structure and could be preferentially internalized along with cell debris by glioma cells via active macropinocytosis. Through this cellular uptake pathway, the lipoplex avoided being entrapped by lysosome and released siRNA in cytoplasm within 4 h, inducing substantial downregulation of c-Myc mRNA and protein expression of glioma cells. Furthermore, due to significantly enhanced permeability in tumor spheroids and nasal mucosa, the lipoplex was competent to deliver more siRNA to orthotopic glioma after intranasal administration, and therefore prolonged the survival time of glioma-bearing mice by inducing apoptosis. STATEMENT OF SIGNIFICANCE: In the present work, a lipoplex was designed to address the unmet demands on intranasal siRNA delivery to the brain for treatment of glioma. First, a powerful peptide was selected to enable the lipoplex to penetrate nasal mucosa. Second, we found the lipoplex could be selectively internalized along with cell debris by glioma cells via active macropinocytosis, and recorded the entire process. This cellular uptake pathway not only prevented the lipoplex being entrapped by lysosome, but also increased distribution of the lipoplex in orthotopic glioma. Third, this lipoplex provided additional protection for siRNA to avoid premature release during transport from nasal to brain. Overall, this lipoplex improved the gene delivery efficiency of intranasal administration and was promising in the perspective of selectively silencing disease-related genes in intracranial tumor.