Leveraging adrenergic receptor blockade for enhanced nonalcoholic fatty liver disease treatment via a biomimetic nanoplatform.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation, steatosis and fibrosis. Sympathetic nerves play a critical role in maintaining hepatic lipid homeostasis and regulating fibrotic progression through adrenergic receptors expressed by hepatocytes and hepatic stellate cells; however, the use of sympathetic nerve-focused strategies for the treatment of NAFLD is still in the infancy. Herein, a biomimetic nanoplatform with ROS-responsive and ROS-scavenging properties was developed for the codelivery of retinoic acid (RA) and the adrenoceptor antagonist labetalol (LA). The nanoplatform exhibited improved accumulation and sufficient drug release in the fibrotic liver, thereby achieving precise codelivery of drugs. Integration of adrenergic blockade effectively interrupted the vicious cycle of sympathetic nerves with hepatic stellate cells (HSCs) and hepatocytes, which not only combined with RA to restore HSCs to a quiescent state but also helped to reduce hepatic lipid accumulation. We demonstrated the excellent ability of the biomimetic nanoplatform to ameliorate liver inflammation, fibrosis and steatosis. Our work highlights the tremendous potential of a sympathetic nerve-focused strategy for the management of NAFLD and provides a promising nanoplatform for the treatment of NAFLD.

Regulating tumor innervation by nanodrugs potentiates cancer immunochemotherapy and relieve chemotherapy-induced neuropathic pain.

Sympathetic nerves play a pivotal role in promoting tumor growth through crosstalk with tumor and stromal cells. Chemotherapy exacerbates the infiltration of sympathetic nerves into tumors, thereby providing a rationale for inhibiting sympathetic innervation to enhance chemotherapy. Here, we discovered that doxorubicin increases the density and activity of sympathetic nerves in breast cancer mainly by upregulating the expression of nerve growth factors (NGFs) in cancer cells. To address this, we developed a combination therapy by co-encapsulating small interfering RNA (siRNA) and doxorubicin within breast cancer-targeted poly (lactic-co-glycolic acid) (PLGA) nanoparticles, aiming to suppress NGF expression post-chemotherapy. Incorporating NGF blockade into the nanoplatform for chemotherapy effectively mitigated the chemotherapy-induced proliferation of sympathetic nerves. This not only bolstered the tumoricidal activity of chemotherapy, but also amplified its stimulatory impact on the antitumor immune response by increasing the infiltration of immunostimulatory cells into tumors while concurrently reducing the frequency of immunosuppressive cells. Consequently, the combined nanodrug approach, when coupled with anti-PD-L1 treatment, exhibited a remarkable suppression of primary and deeply metastatic tumors with minimal systematic toxicity. Importantly, the nanoplatform relieved chemotherapy-induced peripheral neuropathic pain (CIPNP) by diminishing the expression of pain mediator NGFs. In summary, this research underscores the significant potential of NGF knockdown in enhancing immunochemotherapy outcomes and presents a nanoplatform for the highly efficient and low-toxicity treatment of breast cancer.

Stealth and pseudo-stealth nanocarriers.

The stealth effect plays a central role on capacitating nanomaterials for drug delivery applications through improving the pharmacokinetics such as blood circulation, biodistribution, and tissue targeting. Here based on a practical analysis of stealth efficiency and a theoretical discussion of relevant factors, we provide an integrated material and biological perspective in terms of engineering stealth nanomaterials. The analysis surprisingly shows that more than 85% of the reported stealth nanomaterials encounter a rapid drop of blood concentration to half of the administered dose within 1 h post administration although a relatively long ß-phase is observed. A term, pseudo-stealth effect, is used to delineate this common pharmacokinetics behavior of nanomaterials, that is, dose-dependent nonlinear pharmacokinetics because of saturating or depressing bio-clearance of reticuloendothelial system (RES). We further propose structural holism can be a watershed to improve the stealth effect; that is, the whole surface structure and geometry play important roles, rather than solely relying on a single factor such as maximizing repulsion force through polymer-based steric stabilization (e.g., PEGylation) or inhibiting immune attack through a bio-inspired component. Consequently, engineering delicate structural hierarchies to minimize attractive binding sites, that is, minimal charges/dipole and hydrophobic domain, becomes crucial. In parallel, the pragmatic implementation of the pseudo-stealth effect and dynamic modulation of the stealth effect are discussed for future development.

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. This article surveyed the recent progress and challenges of targeted nanomedicine in managing resistance and toxicity of cisplatin in both fundamental and clinical aspects. Particularly, we focused on three major mechanisms counteracting cisplatin sensitivity (decreased intracellular accumulation, increased cisplatin deactivation, and enhanced DNA repair/translesion synthesis) and correspondingly highlighted a few representative approaches to increase cisplatin sensitivity through improving the intracellular concentration of cisplatin and implementing combination therapy. Moreover, the requirements for future advancements in cisplatin delivery systems are rendered with emphasis on (i) understanding of nano-bio interaction and post-accumulation biological effects instead of overwhelmingly improving tumor accumulation, (ii) development of stimuli-responsive and/or actively-targeted nanomedicines, (iii) optimization of combination therapy, (iv) novel combinations targeting tumor microenvironment and immunotherapy. We postulate that cisplatin-based nanomedicines will continuously advance and potentially revolutionize oncological treatment.

Enzymatically Transformable Polymersome-Based Nanotherapeutics to Eliminate Minimal Relapsable Cancer.

Prevention of metastatic and local-regional recurrence of cancer after surgery remains difficult. Targeting postsurgical premetastatic niche and microresiduals presents an excellent prospective opportunity but is often challenged by poor therapeutic delivery into minimal residual tumors. Here, an enzymatically transformable polymer-based nanotherapeutic approach is presented that exploits matrix metalloproteinase (MMP) overactivation in tumor-associated tissues to guide the codelivery of colchicine (microtubule-disrupting and anti-inflammatory agent) and marimastat (MMP inhibitor). The dePEGylation of polymersomes catalyzed by MMPs not only exposes the guanidine moiety to improve tissue/cell-targeting/retention to increase bioavailability, but also differentially releases marimastat and colchicine to engage their extracellular (MMPs) and intracellular (microtubules) targets of action, respectively. In primary tumors/overt metastases, the vasculature-specific targeting of nanotherapeutics can function synchronously with the enhanced permeability and retention effect to deter malignant progression of metastatic breast cancer. After the surgical removal of large primary tumors, nanotherapeutic agents are localized in the premetastatic niche and at the site of the postsurgical wound, disrupting the premetastatic microenvironment and eliminating microresiduals, which radically reduces metastatic and local-regional recurrence. The findings suggest that nanotherapeutics can safely widen the therapeutic window to resuscitate colchicine and MMP inhibitors for other inflammatory disorders.

Therapeutic Polymersome Nanoreactors with Tumor-Specific Activable Cascade Reactions for Cooperative Cancer Therapy.

Therapeutic nanoreactors are of increasing interest in precise cancer therapy, which have been explored to in situ produce therapeutic compounds from inert prodrugs or intrinsic molecules at the target sites. However, engineering a nanoreactor with tumor activable cascade reactions for efficient cooperative cancer therapy remains a great challenge. Herein, we demonstrate a polymersome nanoreactor with tumor acidity-responsive membrane permeability to activate cascade reactions for orchestrated cooperative cancer treatment. The nanoreactors are constructed from responsive polyprodrug polymersomes incorporating ultrasmall iron oxide nanoparticles and glucose oxidase in the membranes and inner aqueous cavities, respectively. The cascade reactions including glucose consumption to generate H2O2, accelerated iron ion release, Fenton reaction between H2O2 and iron ion to produce hydroxyl radicals (•OH), and •OH-triggered rapid release of parent drugs can be specifically activated by the tumor acidity-responsive membrane permeability. During this process, the orchestrated cooperative cancer therapy including starving therapy, chemodynamic therapy, and chemotherapy is realized for high-efficiency tumor suppression by the in situ consumed and produced compounds. The nanoreactor design with tumor-activable cascade reactions represents an insightful paradigm for precise cooperative cancer therapy.

Influence of g-C3N4 nanosheets on thermal stability and mechanical properties of biopolymer electrolyte nanocomposite films: a novel investigation.

A series of sodium alginate (SA) nanocomposite films with different loading levels of graphitic-like carbon nitride (g-C3N4) were fabricated via the casting technique. The structure and morphology of nanocomposite films were investigated by X-ray powder diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, and transmission electron microscopy. Thermogravimetric analysis results suggested that thermal stability of all the nanocomposite films was enhanced significantly, including initial thermal degradation temperature increased by 29.1 °C and half thermal degradation temperature improved by 118.2 °C. Mechanical properties characterized by tensile testing and dynamic mechanical analysis measurements were also reinforced remarkably. With addition of 6.0 wt % g-C3N4, the tensile strength of SA nanocomposite films was dramatically enhanced by 103%, while the Young's modulus remarkably increased from 60 to 3540 MPa. Moreover, the storage modulus significantly improved by 34.5% was observed at loadings as low as 2.0 wt %. These enhancements were further investigated by means of differential scanning calorimetry and real time Fourier transform infrared spectra. A new perspective of balance was proposed to explain the improvement of those properties for the first time. At lower than 1.0 wt % loading, most of the g-C3N4 nanosheets were discrete in the SA matrix, resulting in improved thermal stability and mechanical properties; above 1.0 wt % and below 6.0 wt % content, the aggregation was present in SA host coupled with insufficient hydrogen bondings limiting the barrier for heat and leading to the earlier degradation and poor dispersion; at 6.0 wt % addition, the favorable balance was established with enhanced thermal and mechanical performances. However, the balance point of 2.0 wt % from dynamic mechanical analysis was due to combination of temperature and agglomeration. The work may contribute to a potential research approach for other nanocomposites.