Pharmacological Functions, Synthesis, and Delivery Progress for Collagen as Biodrug and Biomaterial.

Collagen has been widely applied as a functional biomaterial in regulating tissue regeneration and drug delivery by participating in cell proliferation, differentiation, migration, intercellular signal transmission, tissue formation, and blood coagulation. However, traditional extraction of collagen from animals potentially induces immunogenicity and requires complicated material treatment and purification steps. Although semi-synthesis strategies such as utilizing recombinant E. coli or yeast expression systems have been explored as alternative methods, the influence of unwanted by-products, foreign substances, and immature synthetic processes have limited its industrial production and clinical applications. Meanwhile, macromolecule collagen products encounter a bottleneck in delivery and absorption by conventional oral and injection vehicles, which promotes the studies of transdermal and topical delivery strategies and implant methods. This review illustrates the physiological and therapeutic effects, synthesis strategies, and delivery technologies of collagen to provide a reference and outlook for the research and development of collagen as a biodrug and biomaterial.

Phytochemicals as new therapeutic candidates simultaneously stimulate proliferation and counteract senescence of stem cells.

Mesenchymal stem cells (MSCs) are promising candidates for regenerative therapy. However, the research and clinical application of MSCs are greatly hindered by the limited cells proliferation and replicative senescence. Therapeutic agents that can both enhance the proliferative ability and decrease the replicative senescence of MSCs are greatly needed, however, not been reported yet. Herein, for the first time, we identified 11 natural compounds from medicinal plants with both excellent proliferative and anti-senescence abilities in MSCs. The qPCR analysis indicated underlying mechanisms associated with fibroblast growth factor, transforming growth factor, Wnt/ß-catenin and leukemia-induced factor in proliferation; the reactive oxygen species production, mitochondrial dysfunction autophagy and proteostasis are involved in cells senescence-related mechanism. Phytochemicals are demonstrated as novel therapeutic candidates with promising effects in both stimulating proliferation and retarding replicative senescence of stem cells with high safety.

Gene delivery strategies for therapeutic proteins production in plants: Emerging opportunities and challenges.

There are sharply rising demands for pharmaceutical proteins, however shortcomings associated with traditional protein production methods are obvious. Genetic engineering of plant cells has gained importance as a new strategy for protein production. But most current genetic manipulation techniques for plant components, such as gene gun bombardment and Agrobacterium mediated transformation are associated with irreversible tissue damage, species-range limitation, high risk of integrating foreign DNAs into the host genome, and complicated handling procedures. Thus, there is urgent expectation for innovative gene delivery strategies with higher efficiency, fewer side effect, and more practice convenience. Materials based nanovectors have established themselves as novel vehicles for gene delivery to plant cells due to their large specific surface areas, adjustable particle sizes, cationic surface potentials, and modifiability. In this review, multiple techniques employed for plant cell-based genetic engineering and the applications of nanovectors are reviewed. Moreover, different strategies associated with the fusion of nanotechnology and physical techniques are outlined, which immensely augment delivery efficiency and protein yields. Finally, approaches that may overcome the associated challenges of these strategies to optimize plant bioreactors for protein production are discussed.

Mechanical stretching of cells and lipid nanoparticles for nucleic acid delivery.

Gene therapy has gained popularity in the treatment of incurable diseases. However, cell components, such as surface membrane, cytoskeleton protein, and nuclear envelope, retard the transport of nucleic acids, lowering the transfection efficiency. We developed a physical-chemical hybrid platform (S-RCLs) involving cationic lipid nanoparticles (RCLs) exposed to cyclic stretch. The transfection efficiency and delivery mechanisms of S-RCLs for siRNAs and pDNAs (plasmid DNAs encoding luciferase) were investigated. S-RCLs effectively delivered both siRNAs and pDNAs by overcoming the cell barriers. Mechanistically, S-RCLs promote the cellular uptake mediated by CD44, EH-domain containing 2 (EHD2), and caveolin-1 (CAV-1); intracellular transport via MAP6 Domain Containing 1 (Map6d1) and F-actin; and DNA transcription regulated by LSM3 and Hist1h3e in the nucleus. Thus, S-RCLs are a promising hybrid platform with excellent efficiency and biocompatibility for gene delivery both in vitro and in vivo.

Plant Exosome-like Nanovesicles: Emerging Therapeutics and Drug Delivery Nanoplatforms.

Plant exosome-like nanovesicles, being innately replete with bioactive lipids, proteins, RNA, and other pharmacologically active molecules, offer unique morphological and compositional characteristics as natural nanocarriers. Furthermore, their compelling physicochemical traits underpin their modulative role in physiological processes, all of which have fostered the concept that these nanovesicles may be highly proficient in the development of next-generation biotherapeutic and drug delivery nanoplatforms to meet the ever-stringent demands of current clinical challenges. This review systemically deals with various facets of plant exosome-like nanovesicles ranging from their origin and isolation to identification of morphological composition, biological functions, and cargo-loading mechanisms. Efforts are made to encompass their biotherapeutic roles by elucidating their immunological modulating, anti-tumor, regenerative, and anti-inflammatory roles. We also shed light on re-engineering these nanovesicles into robust, innocuous, and non-immunogenic nanovectors for drug delivery through multiple stringent biological hindrances to various targeted organs such as intestine and brain. Finally, recent advances centered around plant exosome-like nanovesicles along with new insights into transdermal, transmembrane and targeting mechanisms of these vesicles are also elucidated. We expect that the continuing development of plant exosome-like nanovesicle-based therapeutic and delivery nanoplatforms will promote their clinical applications.

Outer membrane vesicles derived from E. coli as novel vehicles for transdermal and tumor targeting delivery.

Transdermal drug delivery is favored in clinical therapy because of its ability to overcome the shortcomings of the first pass elimination of the liver caused by traditional oral administration and the irreversibility of the injection. However, skin stratum corneum (SC) forms a big barrier that precludes most of the biomacromolecules. Herein, we propose the engineering of transformed Escherichia coli (E. coli) derived outer membrane vesicles, detoxified by lysozymes (named TEVs) as the carrier for transdermal drug delivery. TEVs were derived from transgenic E. coli and then modified by an integrin alpha(v)beta(3) (αvß3) targeting peptide and co-loaded with indocyanine green (ICG) (P-TEVs-G). TEVs were shown to have excellence in penetrating through intact SC without any additional enhancement, followed by targeting of melanoma cells. TEVs are promising nanoplatforms for transdermal and tumor targeting drug delivery with high efficacy and biosafety, possessing great potential in the treatment of superficial tumors.