Chemically Modified Platforms for Better RNA Therapeutics.

RNA-based therapies have catalyzed a revolutionary transformation in the biomedical landscape, offering unprecedented potential in disease prevention and treatment. However, despite their remarkable achievements, these therapies encounter substantial challenges including low stability, susceptibility to degradation by nucleases, and a prominent negative charge, thereby hindering further development. Chemically modified platforms have emerged as a strategic innovation, focusing on precise alterations either on the RNA moieties or their associated delivery vectors. This comprehensive review delves into these platforms, underscoring their significance in augmenting the performance and translational prospects of RNA-based therapeutics. It encompasses an in-depth analysis of various chemically modified delivery platforms that have been instrumental in propelling RNA therapeutics toward clinical utility. Moreover, the review scrutinizes the rationale behind diverse chemical modification techniques aiming at optimizing the therapeutic efficacy of RNA molecules, thereby facilitating robust disease management. Recent empirical studies corroborating the efficacy enhancement of RNA therapeutics through chemical modifications are highlighted. Conclusively, we offer profound insights into the transformative impact of chemical modifications on RNA drugs and delineates prospective trajectories for their future development and clinical integration.

[CiteSpace knowledge map of research hotspots and frontiers of traditional Chinese medicine intervention in psoriasis in recent ten years].

This study aimed to investigate the development status of traditional Chinese medicine(TCM) intervention in psoriasis in recent ten years, analyze the research hotspots, and summarize the development trends to provide reference materials for scholars in this field. Taking the available literature related to the field of TCM intervention in psoriasis as the research object, the trends, contents, and source publications were statistically analyzed based on bibliometrics. The research cooperation and co-occurrence of keywords in this field were studied by the knowledge map analysis method based on CiteSpace. The total number of Chinese papers was 2 993 and English papers 285. In terms of publication trend, the annual publication of English papers was low but showed an obvious upward trend, while the increase in Chinese papers fluctuated and tended to be flat. In terms of the content of Chinese papers published, TCM ranked first according to the discipline(2 415). In English papers, the number of publications in pharmacology and pharmaceutical science was the highest(87). Literature source analysis showed that the Chinese and English journals with the most publications were China Journal of Traditional Chinese Medicine and Pharmacy and Evidence Based Complementary and Alternative Medicine, respectively. Beijing University of Chinese Medicine published the most dissertations in China(99). The authors with the most publications in Chinese and English were LI Bin(Yueyang Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Shanghai University of Traditional Chinese Medicine) and LU Chuan-jian(Guangdong Hospital of Traditional Chinese Medicine). As revealed by the CiteSpace analysis of the research cooperation network, there were four mature and stable core teams in this field, but the cooperation intensity between different teams was weak. According to the keywords co-occurrence knowledge graph constructed by CiteSpace, the current hot keywords in this field are as follows: psoriasis, blood-heat syndrome, blood-stasis syndrome, fire needle, blood-dryness type, imiquimod, TCM bath, etiology and pathogenesis, cytokines, cupping therapy, etc. In summary, Chinese scholars have conducted active exploration and research in the field of TCM intervention in psoriasis in recent ten years. The overall development trend is good, and the breadth and depth of the research are constantly extending. It is suggested that relevant research should be free from discipline restrictions and strive for interdisciplinary integration.

Biointerface-Engineered Hybrid Nanovesicles for Targeted Reprogramming of Tumor Microenvironment.

The tumor microenvironment (TME) of typical tumor types such as triple-negative breast cancer is featured by hypoxia and immunosuppression with abundant tumor-associated macrophages (TAMs), which also emerge as potential therapeutic targets for antitumor therapy. M1-like macrophage-derived exosomes (M1-Exos) have emerged as a promising tumor therapeutic candidate for their tumor-targeting and macrophage-polarization capabilities. However, the limited drug-loading efficiency and stability of M1-Exos have hindered their effectiveness in antitumor applications. Here, a hybrid nanovesicle is developed by integrating M1-Exos with AS1411 aptamer-conjugated liposomes (AApt-Lips), termed M1E/AALs. The obtained M1E/AALs are loaded with perfluorotributylamine (PFTBA) and IR780, as P-I, to construct P-I@M1E/AALs for reprogramming TME by alleviating tumor hypoxia and engineering TAMs. P-I@M1E/AAL-mediated tumor therapy enhances the in situ generation of reactive oxygen species, repolarizes TAMs toward an antitumor phenotype, and promotes the infiltration of T lymphocytes. The synergistic antitumor therapy based on P-I@M1E/AALs significantly suppresses tumor growth and prolongs the survival of 4T1-tumor-bearing mice. By integrating multiple treatment modalities, P-I@M1E/AAL nanoplatform demonstrates a promising therapeutic approach for overcoming hypoxic and immunosuppressive TME by targeted TAM reprogramming and enhanced tumor photodynamic immunotherapy. This study highlights an innovative TAM-engineering hybrid nanovesicle platform for the treatment of tumors characterized by hypoxic and immunosuppressive TME.

Precise assembly of inside-out cell membrane camouflaged nanoparticles via bioorthogonal reactions for improving drug leads capturing.

Cell membrane camouflaged nanoparticles have been widely used in the field of drug leads discovery attribute to their unique biointerface targeting function. However, random orientation of cell membrane coating does not guarantee effective and appropriate binding of drugs to specific sites, especially when applied to intracellular regions of transmembrane proteins. Bioorthogonal reactions have been rapidly developed as a specific and reliable method for cell membrane functionalization without disturbing living biosystem. Herein, inside-out cell membrane camouflaged magnetic nanoparticles (IOCMMNPs) were accurately constructed via bioorthogonal reactions to screen small molecule inhibitors targeting intracellular tyrosine kinase domain of vascular endothelial growth factor recptor-2. Azide functionalized cell membrane acted as a platform for specific covalently coupling with alkynyl functionalized magnetic Fe3O4 nanoparticles to prepare IOCMMNPs. The inside-out orientation of cell membrane was successfully verified by immunogold staining and sialic acid quantification assay. Ultimately, two compounds, senkyunolide A and ligustilidel, were successfully captured, and their potential antiproliferative activities were further testified by pharmacological experiments. It is anticipated that the proposed inside-out cell membrane coating strategy endows tremendous versatility for engineering cell membrane camouflaged nanoparticles and promotes the development of drug leads discovery platforms.

Bioinspired nano-plate-coral platform enabled efficient detection of circulating tumor cells via the synergistic capture of multivalent aptamer and tumor cell membrane.

Circulating tumor cells (CTCs) offer rich information for early disease diagnosis and therapy evaluation. However, the limited sensitivity, binding affinity, and stability of current monovalent recognition-based CTCs detection techniques remain a challenge for extending their applications. Inspired by the highly efficient predation manner of plate corals, we firstly introduce an efficient and sensitive biomimetic CTCs recognition platform based on the conjugation of multivalent aptamer onto tumor cell membrane-coated magnetic graphene oxide to form a plate coral-like CTCs capture nanoprobe (MNPA-TCMMGO). In this method, the tumor cell membrane was employed to provide a biomimetic homologous fluidic interface for targeting homologous tumor cells. At the same time, multivalent aptamers were used as capture probes, which greatly enhanced the binding affinity and association probability between aptamer and target cells via cooperative multivalent effect. The unique features (robustness, high binding affinity and specificity, and biocompatibility) of MNPA-TCMMGO allow efficient, sensitive, and specific capture of rare tumor cells from biological samples. More importantly, the captured cells could maintain good viability, which is crucial for downstream analysis. Therefore, our developed biomimetic approach offers a new way to address the limitations of current CTCs detection methods and presents considerable potential for clinical cancer diagnostics.

Hybrid biointerface engineering nanoplatform for dual-targeted tumor hypoxia relief and enhanced photodynamic therapy.

The clinical application of photodynamic therapy (PDT) is limited by the lack of tumor selectivity of photosensitizer (PS) and the hypoxic tumor microenvironment (TME). To address these limitations of PDT, we developed a hybrid engineered biointerface nanoplatform that integrated anti-epidermal growth factor receptor (EGFR)-aptamer (EApt)-modified liposomes with tumor cell membranes (TMs) to create M/L-EApt. M/L-EApt exhibited enhanced stability and significant dual-targeting ability, enabling selectively accumulate in hypoxic tumor regions after systemic infusion. PHI@M/L-EApt, formed by M/L-EApt loaded with an oxygen carrier perfluorotributylamine (PFTBA) and IR780 (a PS), effectively promoted the therapeutic performance of PDT by reversing the hypoxic TME and increasing the accumulation of IR780 at the tumor sites, resulting in a robust anti-tumor efficacy. In vivo results showed that PHI@M/L-EApt treatment effectively suppressed the growth of triple-negative breast tumors in mice. Our findings demonstrated the synergistic effect of oxygen supply and PDT on tumor treatment using PHI@M/L-EApt. This study presented a biomimetic interface engineering strategy and dual-targeted hybrid nanoplatform for relieving hypoxic TME and potentially facilitating the clinical application of PDT.

Nanosensitizer-mediated augmentation of sonodynamic therapy efficacy and antitumor immunity.

The dense stroma of desmoplastic tumor limits nanotherapeutic penetration and hampers the antitumor immune response. Here, we report a denaturation-and-penetration strategy and the use of tin monosulfide nanoparticles (SnSNPs) as nano-sonosensitizers that can overcome the stromal barrier for the management of desmoplastic triple-negative breast cancer (TNBC). SnSNPs possess a narrow bandgap (1.18 eV), allowing for efficient electron (e-)-hole (h+) pair separation to generate reactive oxygen species under US activation. More importantly, SnSNPs display mild photothermal properties that can in situ denature tumor collagen and facilitate deep penetration into the tumor mass upon near-infrared irradiation. This approach significantly enhances sonodynamic therapy (SDT) by SnSNPs and boosts antitumor immunity. In mouse models of malignant TNBC and hepatocellular carcinoma (HCC), the combination of robust SDT and enhanced cytotoxic T lymphocyte infiltration achieves remarkable anti-tumor efficacy. This study presents an innovative approach to enhance SDT and antitumor immunity using the denaturation-and-penetration strategy, offering a potential combined sono-immunotherapy approach for the cancer nanomedicine field.

Nano-bio interactions in mRNA nanomedicine: Challenges and opportunities for targeted mRNA delivery.

Upon entering the biological milieu, nanomedicines swiftly interact with the surrounding tissue fluid, subsequently being enveloped by a dynamic interplay of biomacromolecules, such as carbohydrates, nucleic acids, and cellular metabolites, but with predominant serum proteins within the biological corona. A notable consequence of the protein corona phenomenon is the unintentional loss of targeting ligands initially designed to direct nanomedicines toward particular cells or organs within the in vivo environment. mRNA nanomedicine displays high demand for specific cell and tissue-targeted delivery to effectively transport mRNA molecules into target cells, where they can exert their therapeutic effects with utmost efficacy. In this review, focusing on the delivery systems and tissue-specific applications, we aim to update the nanomedicine population with the prevailing and still enigmatic paradigm of nano-bio interactions, a formidable hurdle in the pursuit of targeted mRNA delivery. We also elucidate the current impediments faced in mRNA therapeutics and, by contemplating prospective avenues-either to modulate the corona or to adopt an 'ally from adversary' approach-aim to chart a course for advancing mRNA nanomedicine.

Rational construction of fluorescent molecular imprinted polymers for highly efficient glycoprotein detection.

The enrichment of glycoproteins by fluorescence molecular imprinting has shown an attractive application prospect, however, its specificity and sensitivity in actual sample analysis remain a significant challenge. In this work, a novel fluorescent molecular imprinted nanoplatform (MMIPs@QDs) was constructed for the efficient recognition and determination of glycoproteins by combining the glycopeptide template and the post-imprinting modification of nitrogen-doped graphene quantum dots. The synthetic MMIPs@QDs exhibited high adsorption capacity and rapid binding kinetics. Satisfying selectivity and sensitivity were obtained using MMIPs@QDs, with an imprinting factor of 7.71 and a limit of detection of 0.20 µg mL-1, respectively. The efficiency and applicability of this proposed method were validated by the detection of ovalbumin in egg white samples, showed high recoveries (94.3%-100.2%) and acceptable relative standard deviation (1.79%-7.36%). This fluorescent molecular imprinted nanoplatform provides a new approach to address the limitations of existing protein detection techniques.

Surface functionalized biomimetic bioreactors enable the targeted starvation-chemotherapy to glioma.

Altering the glucose supply and the metabolic pathways would be an intriguing strategy in starvation therapy toward cancers. Nevertheless, starvation therapy alone could be inadequate to eliminate tumor cells completely. Herein, a multifunctional bioreactor was fabricated for synergistic starvation-chemotherapy through embedding glucose oxidase (GOx) and doxorubicin (DOX) in the tumor targeting ligands (RGD) modified red blood cell membrane camouflaged metal-organic framework (MOF) nanoparticle (denoted as RGD-mGZD). Owing to the remarkable biointerfacing property, the designed RGD-mGZD could not only possess enhanced blood retention time inherited from red blood cells, but also preferentially target the tumor site after the modification with RGD peptide. Once the bioreactor reached the desired region, GOx promptly consumed the intratumoral glucose and oxygen to starve cancer cells for robust starvation therapy. More importantly, the aggravated acidic microenvironment at the tumor region was found to induce the decomposition of the MOF structure, thus triggering the release of DOX for reinforced chemotherapy. This bioreactor would further prompt the development of synergistic patterns toward cancer treatment in a spatiotemporally controlled manner.

Engineering biomimetic graphene nanodecoys camouflaged with the EGFR/HEK293 cell membrane for targeted capture of drug leads.

Advanced graphene (G)-based nanomaterials have risen as emerging stars for biomedical applications over the past decade due to their unique physicochemical properties. However, the preparation of G-based nanomaterials with satisfactory bioactivity to meet the growing demands of multitasking applications in biocomplexity systems remains a challenge. Herein, we presented a biomimetic route to modify graphene oxide (GO) using high expression epidermal growth factor receptor cell membrane (CM). Owing to the inherent properties of the CM for multifaceted interaction with active ligands, the well camouflaged GO could capture the drug leads with targeting properties. The as-prepared CM-coated magnetic GO exhibited excellent binding properties, including good selectivity, high adsorption capacity, and suitable adsorption rates. In addition, by coupling this assay with mass spectrometry, two potential bioactive compounds, luteolin and caffeic acid, were screened from Taraxacum mongolicum Hand.-Mazz. It is anticipated that this biomimetic approach can open new possibilities for the rational design of improved G-based biocomposites and extend their bioapplications.

Neonatal infection-associated mortality in China, a population-based study, 2003-2008.

OBJECTIVE: To examine trends in the major causes and rates of neonatal infection-associated mortality (NIMRs) in different geographical regions in China from 2003 to 2008. METHODS: Neonatal mortality data collected from the Chinese National Women and Children's Health Surveillance Network were analyzed. RESULTS: The NIMRs declined. Pneumonia, sepsis and diarrhea were the top three infections that caused neonatal deaths. Compared to the coastal region, the relative risk (RR) of NIMRs in the remote and inland regions declined from 5.52 (95% CI: 4.05-7.52) and 2.37 (95% CI: 1.72-3.25) during 2003-2005 to 3.45 (95% CI: 2.58-4.61) and 1.72 (95% CI: 1.28-2.31) during 2006-2008, respectively. Once again, compared to the coastal region, the risk of pneumonia-specific mortality had significant regional disparities during 2006-2008 with a RR of 3.82 (95% CI: 2.74-5.32) in the remote region and 2.01 (95% CI: 1.44-2.80) in the inland region. The NIMRs in the remote region was characterized by more home deliveries and non-healthcare seeking behavior prior to death than the coastal region. CONCLUSIONS: Infection is still one of the main causes of neonatal mortality in China. Although the NIMRs have been declining, disparities concerning neonatal infection-associated and pneumonia-specific neonatal morality still exist. Approaches for reducing mortality of neonatal infections will efficiently decrease total neonatal mortality.

[The wax and wane of the trend of "man benefits man" in the late Ming Dynasty].

It was in the period of from Jia Jing to Wan Li Reign that the trend of medication of "man benefits man" appeared with rather great influence in the society. This medication trend experienced a process of rising, zenith, declining, and eventual termination. Among this trend, the refining process of Hong Qian (Red Lead) and Pan Tao Jiu (Mythical Peach Alcohol) was imbued with the ruin of women, arousing debate soon after the trend appeared, with a tit for tat struggle between two medical schools. This research reveals that such medication trend is an adverse current started by fallacious alchemists. Its influence goes beyond the scope of medical field, though its position in the medical province itself is rather low.

[Study on Shi Zhenduo's Ben cao bu (Supplemented materia medica)].

Being called "precursor of pharmacy imported from the west" by Fan Xingzhun, a famous medical historian, Ben cao bu was lost in China. It has been found outside China recently. This article deals with the author, blockprinting edition, contents of the book and makes a comparison with its texts cited in Ben cao gang mu shi yi (Supplemented Compendium of Materia Medica). It also evaluates the practical significance of this book as an early dissemination of pharmacy imported from the west.