Neural stem cells (NSCs) are located in specific regions of the central nervous system called niches. Those cells are able to self-renew and to differentiate into specialized neuronal cells (neurons, astrocytes and oligodendrocytes). Due to this differentiation property, NSCs are studied to replace neuronal cells and restore neurological functions in patients affected by neurodegenerative diseases. Several therapeutic approaches have been developed and endogenous NSC stimulation is one of the most promising. Currently, there is no active molecule or therapeutic system targeting endogenous CSNs and inducing their differentiation at the same time. The aim of the work was to provide a drug delivery system able both to target endogenous CSNs and to induce their differentiation in situ. Here, we developed and characterized lipidic nanoparticles (LNC) targeting endogenous NSCs. A peptide called NFL-TBS.40-63, known for its affinity towards NSCs, was adsorbed at the surface of LNC. We observed that NFL-LNC specifically targeted NSC from the brain and not from the spinal cord in vitro and in vivo. To explain this specificity, we characterized and compared NFL-LNC interactions with the plasmatic membrane of both cell types. Finally, we demonstrated that by loading retinoic acid in NFL-LNC we were able to induce brain NSC differentiation in vitro and in vivo. This work contributes to the development of efficient and safe therapies for the treatment of neurodegenerative disease via the differentiation of endogenous NSCs.

With contributions from leading researchers in the nanomedicine field from industry, academia, and government and private research institutions across the globe, the volume provides an up-to-date report on topical issues in nano-drug delivery and nanotechnological approaches to tissue engineering. The volume offers research on a variety of diverse nano-based drug delivery systems along with discussions of their efficacy, safety, toxicology, and applications for different purposes. Focusing on nanotechnology approaches to tissue engineering, this volume considers the use of hydrogel systems, nanoceria and micro- and nano-structured biomaterials for bone tissue engineering, mesenchymal stem cells, and more.

Topic Editor RL is a patent inventor on exosome-related patents, PCT/AU2017/050821 and PCT/AU2016/050468. All other Topic Editors declare no competing interests with regards to the Research Topic subject.

The realm of nanomedicine, defined as the applications of nanotechnology for medical purposes such as diagnosis, monitoring and treatment of diseases, has grown exponentially over the past few decades; with several research efforts translating into commercial success stories. Such applications requires the amalgamation of research efforts from different disciplines such as chemistry, biology, physics, engineering and clinical medicine. While the earlier efforts in nanomedicine were focused mainly on improving the properties of the available therapeutics, current research efforts are more geared towards developing novel therapeutics or imaging modalities based on the supramolecular assembly of nanoscale building blocks. There is a plethora of nanoscale platforms that are being developed for clinical uses, including, polymeric nanoparticles, liposomes and micelles, metallic nanostructures, semiconductor quantum dots and silicon oxide nanoparticles. However, there are several obstacles that need to be overcome, prior to the wide-spread clinical applications of these nanoparticles, such as (i) developing well-defined nanoparticles of varying size, morphology and composition to enable various clinical applications; (ii) optimization of the biopharmaceutical properties such as physiological stability, solubility and systemic circulation of the nanoparticle-based therapeutics; (iii) delivery of different kinds of therapeutics without altering their pharmacological effects; (iv) overcome various physiological barriers encountered in order to deliver the therapeutics to the target location; and (v) real-time monitoring of the nano-therapeutics within the human body for tracking their uptake, localization and effect. Hence, this dissertation focuses on developing multimodal nanotechnology-based approaches to overcome the above-mentioned challenges by combining either different nanoparticle compositions or different therapeutic moieties, towards a singular purpose of regulating cancer and stem cell fate, such as proliferation, differentiation and cell death. The initial part of this dissertation describes the synthesis and characterization of well-defined and monodisperse multimodal magnetic core-shell nanoparticles (MCNPs), comprised of a highly magnetic core surrounded by a thin gold shell. As a result of combining two different elements (Fe and Au) within a single nanoplatform, these multimodal core-shell nanoparticles possessed both magnetic and plasmonic properties, which allowed for enhanced therapy and imaging. These nanoparticles were utilized for mainly two applications: (i) Magnetically-facilitated delivery of siRNA and plasmid DNA to neural stem cells for inducing neuronal differentiation and non-invasive imaging and (ii) Combined hyperthermia and targeted delivery of a mitochondria-targeting peptide for enhancing apoptosis in brain and breast cancer cells. The following part of this dissertation presents the synthesis and applications of a multi-functional polymeric delivery platform (known as DexAMs), composed of a dendritic cationic polyamine conjugated to a single beta-cyclodextrin moiety. The DexAM molecule was utilized as a single vehicle to simultaneously deliver two orthogonal therapeutics - anticancer drugs and siRNAs against oncogenes, in a target-specific manner to brain tumor cells. This combined delivery of chemotherapeutics and siRNA targeted the multiple dysregulated pathways in cancer cells and this resulted in a synergistic effect on the apoptosis of brain tumor cells, as compared to the individual treatments. The final part of this thesis presents synthesis of stimuli-responsive fluorescence resonance energy transfer (FRET)-based mesoporous silica nanoparticles for real-time monitoring of drug release in cells. These MSNs were composed of a porous silica support which allowed for drug loading, a stimuli-responsive valve composed of disulfide bonds, and a FRET donor-acceptor pair of coumarin and fluorescein integrated within the disulfide bond. The stimuli-responsive valve was cleaved only in the presence of increased glutathione concentrations found within cancer cells, resulting in change in the FRET signal, thus allowing for real time monitoring of drug release. Taken together, these nanomaterial-based approaches combine therapeutic and imaging modalities within a single nanoplatform and as a result have the potential for regulating cancer and stem cell fate such as proliferation, differentiation and apoptosis as well as allowing for real-time monitoring of these events in a non-invasive manner.

This contribution book collects reviews and original articles from eminent experts working in the interdisciplinary arena of novel drug delivery systems and their uses. From their direct and recent experience, the readers can achieve a wide vision on the new and ongoing potentialities of different smart drug delivery systems. Since the advent of analytical techniques and capabilities to measure particle sizes in nanometer ranges, there has been tremendous interest in the use of nanoparticles for more efficient methods of drug delivery. On the other hand, this reference discusses advances in the design, optimization, and adaptation of gene delivery systems for the treatment of cancer, cardiovascular, diabetic, genetic, and infectious diseases, and considers assessment and review procedures involved in the development of gene-based pharmaceuticals.

The recent advances in nanotechnology and nanomedicine and nanoparticle-based drug delivery systems targeting different chronic diseases can offer promising therapeutic and diagnostic abilities allowing specific delivery of the drugs to the targeted tissue and therefore improving drug efficacy and minimizing side effects.Recent advances in the design of engineered nanoparticles have offered new perspectives for novel theranostics capable of improving both the therapy and diagnosis of various diseases in a single multifunctional platform.

Stem cell engineering for regenerative medicine offers new hope for treating many ailments and injuries. Hence, there is an urgent demand by stem cell scientists for an alternative platform that induces stem cell differentiation in a safe and efficient manner. Stem cell differentiation is inherently regulated by transcription factors (TFs), which are multi-domain proteins that interact with DNA to control expression of target genes, and thus, TFs are master regulators of gene expression and cellular behavior. Recently, scientists have developed synthetic transcription factors (STFs), which are small molecules that mimic the function of the individual domains on TF proteins. This work presents the development a novel bio-inspired platform called NanoScript, which is an alternative approach for safe stem cell differentiation. NanoScript is a nanoparticle-based artificial TF protein because it is designed to replicate the function and structure of natural TF proteins. NanoScript was constructed by assembling STFs onto multifunctional nanoparticles. We first demonstrate that NanoScript localizes within the nucleus of cells, initiates transcription of a reporter plasmid by over 15-fold in cancer cells, and transcribes endogenous genes. The tunable and interchangeable components of NanoScript can easily be modified to either activate or deactivate any gene of interest. As a result, NanoScript was then demonstrated for three stem cell-based applications: 1) NanoScript targets myogenic genes to differentiate adipose-derived mesenchymal stem cells (ADMSCs) into muscle cells, 2) NanoScript modified with an epigenetic modulator, CTB, increases transcriptional potency and enhances differentiation of ADMACs into chondrocytes, and 3) NanoScript redesigned with gene repression molecules acts a transcriptional repressor protein because it downregulates gene expression to induce differentiation of neural stem cells into functional neurons. Because of its robust tunability and biocompatibility, the patented NanoScript platform is a promising alternative tool for research scientists for applications involving gene manipulation such as stem cell differentiation, cancer therapy, and cellular reprogramming. Moreover, the ability of NanoScript to induce stem cell differentiation in a non-viral and footprint-free manner is highly desired by stem cell clinicians, and hence, holds potential for use in stem cell-based therapies.