Targeted drug and gene delivery is the key for precision therapy. Lipid nanoparticles as non-viral vectors have attracted extensive attentions in treating a variety of diseases, such as cancer, immune disease, cardiac diseases and pathogen infection. They exhibit low immunogenicity and low cytotoxicity, which make them as the most-commonly used vectors. More importantly, their surfaces could be functionalized, which provide a platform to improve targeting and pharmacokinetic/pharmacodynamic properties. Although there has been great success to synthesize lipid nanoparticles, it remains as a challenge to produce active targeting lipid nanoparticles especially with definable targetability, high quality and good translation reproducibility. This review focus on the techniques to fabricate active targeting lipid nanoparticles. We start with a brief introduction of targeting lipid nanoparticles, followed by a focused discussion of various preparation approaches including one-pot assembly and post-insertion functionalization. The methods, mechanism and representative examples are introduced, together with the comparison of their advantages and restrictions. Finally, challenges facing formulation screening and clinical translation are discussed. • Active targeting lipid nanoparticle is a clinical-available platform for precision nanomedicine. • One-pot assembly strategy allows for feasible fabrication and modulation of targeting ligand density. • Post-insertion strategy makes it possible to conjugate antibodies and other fragile targeting ligands. • Challenges facing clinical translations of active targeting lipid nanoparticles exist. 

Fabrication of active targeting lipid nanoparticles: Challenges and perspectives

siRNA‐based nanotherapeutics as emerging modalities for immune‐mediated diseases: A preliminary review

Recent advances of nanotechnology application in autoimmune diseases – A bibliometric analysis

Abstract Cancer is a complex disease associated with a combination of abnormal physiological process and exhibiting dysfunctions in multiple systems. To provide effective treatment and diagnosis for cancer, current treatment strategies simultaneously focus on various tumor targets. Based on the rapid development of nanotechnology, nanocarriers have been shown to exhibit excellent potential for cancer therapy. Compared with nanoparticles with single functions, multifunctional nanoparticles are believed to be more aggressive and potent in the context of tumor targeting. However, the development of multifunctional nanoparticles is not simply an upgraded version of the original function, but involves a sophisticated system with a proper backbone, optimized modification sites, simple preparation method, and efficient function integration. Despite this, many well‐designed multifunctional nanoparticles with promising therapeutic potential have emerged recently. Here, to give a detailed understanding and analyzation of the currently developed multifunctional nanoparticles, their platform structures with organic or inorganic backbones were systemically generalized. We emphasized on the functionalization and modification strategies, which provide additional functions to the nanoparticle. We also discussed the application combination strategies that were involved in the development of nanoformulations with functional crosstalk. This review thus provides an overview of the construction strategies and application advances of multifunctional nanoparticles.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/mco2.187

Multifunctional nanoparticle for cancer therapy

mRNA‐based gene therapy has emerged as an advanced strategy for hepatocellular carcinoma (HCC) treatment. However, one of its main limitations is lacking delivery precision in vivo. Distinguishing HCC cells from other tissues is crucial for maintaining the high stability, positive therapeutic outcomes, and safety of mRNA therapeutics. Here, a novel HCC specific peptide HCC167 is developed by phage display. It is shown that the HCC167 peptide can specifically recognize variety of HCC substrates including patient samples with high affinity. Modifying nanoparticles with the HCC167 peptide facilitates an effective HCC active targeting ability. When loading with Bims‐encoding mRNA, the systemically administrated DMP‐HCC167/Bims complex efficiently suppresses HCC progression in multiple models including patient‐derived xenografts. Furthermore, the ALPPL2 protein is identified as a specific binding receptor of the HCC167 peptide on the HCC cell membrane, uncovering a new active targeting mechanism based on the HCC167‐ALPPL2 ligand–receptor complex. The binding structure is also investigated by computer‐aided modeling. The study hence exhibits a potent active targeting strategy for mRNA‐based HCC therapy.

ALPPL2‐Binding Peptide Facilitates Targeted mRNA Delivery for Efficient Hepatocellular Carcinoma Gene Therapy

Abstract The outbreak of COVID-19 has become a global crisis, and brought severe disruptions to societies and economies. Until now, effective therapeutics against COVID-19 are in high demand. Along with our improved understanding of the structure, function, and pathogenic process of SARS-CoV-2, many small molecules with potential anti-COVID-19 effects have been developed. So far, several antiviral strategies were explored. Besides directly inhibition of viral proteins such as RdRp and M pro , interference of host enzymes including ACE2 and proteases, and blocking relevant immunoregulatory pathways represented by JAK/STAT, BTK, NF-κB, and NLRP3 pathways, are regarded feasible in drug development. The development of small molecules to treat COVID-19 has been achieved by several strategies, including computer-aided lead compound design and screening, natural product discovery, drug repurposing, and combination therapy. Several small molecules representative by remdesivir and paxlovid have been proved or authorized emergency use in many countries. And many candidates have entered clinical-trial stage. Nevertheless, due to the epidemiological features and variability issues of SARS-CoV-2, it is necessary to continue exploring novel strategies against COVID-19. This review discusses the current findings in the development of small molecules for COVID-19 treatment. Moreover, their detailed mechanism of action, chemical structures, and preclinical and clinical efficacies are discussed. 

/pdf/small-molecules-in-the-treatment-of-covid-19-313d7e1y.pdf

Small molecules in the treatment of COVID-19

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases worldwide, causing severe cartilage damage and disability. Despite the recent progress made in RA treatment, limitations remain in achieving early and efficient therapeutic intervention. Advanced therapeutic strategies are in high demand, and siRNA-based therapeutic technology with a gene-silencing ability represents a new approach for RA treatment. In this study, we created a cationic delivery micelle consisting of low-molecular-weight (LMW) polyethylenimine (PEI)–cholesterol–polyethylene glycol (PEG) (LPCE) for small interfering RNA (siRNA)-based RA gene therapy. The carrier is based on LMW PEI and modified with cholesterol and PEG. With these two modifications, the LPCE micelle becomes multifunctional, and it efficiently delivered siRNA to macrophages with a high efficiency greater than 70%. The synthesized LPCE exhibits strong siRNA protection ability and high safety. By delivering nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 siRNA, the p65 siRNA/LPCE complex efficiently inhibited macrophage-based cytokine release in vitro. Local administration of the p65 siRNA/LPCE complex exhibited a fast and potent anti-inflammatory effect against RA in a mouse model. According to the results of this study, the functionalized LPCE micelle that we prepared has potential gene therapeutic implications for RA.

/pdf/efficient-treatment-of-rheumatoid-arthritis-by-degradable-1k4pxkl1.pdf

Efficient Treatment of Rheumatoid Arthritis by Degradable LPCE Nano-Conjugate-Delivered p65 siRNA

http://manuscript.elsevier.com/S0168365922000967/pdf/S0168365922000967.pdf

Dual-RNA controlled delivery system inhibited tumor growth by apoptosis induction and TME activation.

Aiming at properties of remote sensing image data such as high-dimension, nonlinearity and massive unlabeled samples, a kind of probability least squares support vector machine (PLSSVM) classification method based on hybrid entropy and L1 norm was proposed. Firstly, hybrid entropy was designed by combining quasi-entropy with entropy difference, which was used to select the most “valuable” samples to be labeled from massive unlabeled sample set. Secondly, a L1 norm distance measuring was used to further select and remove outliers and redundant data from the sample set to be labeled. Finally, based on originally labeled samples and screened samples, PLSSVM was gained through training. Experimental results on classification of ROSIS hyperspectral remote sensing images show that the overall accuracy and Kappa coefficient of the proposed classification method reach higher accuracy respectively. The proposed method can obtain higher classification accuracy with few training samples, which is much applicable to classification problem of remote sensing images.

Xiao-hui Chen

Papers

Small molecules in the treatment of COVID-19

Efficient Treatment of Rheumatoid Arthritis by Degradable LPCE Nano-Conjugate-Delivered p65 siRNA

ALPPL2‐Binding Peptide Facilitates Targeted mRNA Delivery for Efficient Hepatocellular Carcinoma Gene Therapy

Dual-RNA controlled delivery system inhibited tumor growth by apoptosis induction and TME activation.

Image Classification via Active Learning and Probability Least Squares Support Vector Machine