This special issue is dedicated to nanomedicine and aimed to combine the expertise of a large number of scientists worldwide with extensive experience in nanomedicine, but also to discuss how fostering basic science into translational and personalized medicine for drug delivery applications. This can be achieved by a cutting-edge and multidisciplinary field of nanomedicine focused on innovative advancements to develop precise targeting strategies and unlock nanomedicine potentialities for precision medicine and relevant pre-clinical and clinical applications for different medical diseases.
Nanomedicine is the medical application of nanotechnology and includes the combination of nano- and bio-materials at nanometer scale to manufacture scalable advanced drug delivery systems and medical devices in the perspective to address different pathologies in a complex and heterogeneous scenario [1]. The combination of nanomaterials properties, as well as the selectively targeting of microenvironment and tissue through physiological and pathological mechanisms, can modulate the micro- and macro-environments of the diseases in patients affected by rare and clinically relevant pathologies; thus providing specific properties for tailoring precision medicine, and boosting the application for many diseases with suitable therapeutic options and benefits for the patients [2]. The chemical, physical and biological targeting of nanomedicine unlock their potentiality and led to their development as diagnostic/medical devices, contrast agents, analytical tools, physical therapeutic agents, and drug delivery systems [3,4,5].
This special issue seeks to deliver a valuable set of research tools and clinically useful devices and may foster the translation of nanomedicine from bench to bed side in the perspective of personalized therapy towards a reliable pre-clinical and clinical assessment [6,7,8,9,10]. In this scenario, nanoparticles, with different compositions and interface properties, may foster the translation of basic science in personalized nanomedicines for different therapeutic application and provide a significant impact in therapy and treatment of metabolic and non-metabolic diseases.
This special issue on “Unlocking the potential of nanomedicine: advances in precision targeting strategies” addresses a cutting-edge and multidisciplinary field of nanomedicine. For this reason, eminent, expert, and outstanding scientists were invited to contribute with research articles that provide new advancements for precision targeting strategies of nanomedicine and give a snapshot of the evolution of nanomedicine that have gained a significant interest for different clinical applications and medical disease treatments. Expert scientists working in chemistry, biomedical sciences, materials science, biology, and medicine provided suitable and significant contributions in a cross-, multi-, inter-, and trans- disciplinary perspectives to address chemical, biological, material, and clinical properties of nanomedicine, and thus, emphasizing the clinical translation of recently development nanomedicines. These contributions demonstrated the revolutionary impact of nanomedicines in pharmaceutics and biomedicine, as well as their relevant applications in pre-clinical and clinical studies.
This special issue collected 18 amazing contributions, including 4 review papers and 14 full papers, which broadly cover the various important topics within the nanomedicine’s field. The contributions address the impact of nanomedicine in basic science, translational and personalized medicine for the treatment of various diseases.
In the field of hybrid nanoparticles for colon delivery, Prof. Lozano and co-workers from the University Castilla-La Mancha in Albacete (https://doi.org/10.1007/s13346-024-01641-7), developed oral hybrid systems based on nanoemulsions for treatment of ulcerative colitis. This hybrid systems was included in pectin hydrogel matrix that are disassembled in the gastro-intestinal tract and facilitate the stimuli-triggered release of the nanoemulsions at the colon. Results further demonstrated that the condensation process occurred during the synthesis of the hybrid system affects to the enzymatic degradation of pectin as well as the enzyme-triggered release.
Prof. Pozo-Rodríguez and co-workers from the Centro de Investigación Lascaray Ikergunea, University of the Basque Country (https://doi.org/10.1007/s13346-024-01583-0), discussed the targeting strategies by using lipid- based vectors for nucleic acid delivery and their impact in Fabry diseases (FD). The authors discussed the impact of lipid-based systems as non-viral nucleic acid delivery systems, and their versatility to link the surface of a wide range of molecules and control their biodistribution after intravenous administration. This systematic review and meta-analysis provided an overview and discussion of the targeting ligands that was used as active non-viral vectors based on lipid carriers to clinically relevant organs in the treatment of FD, for protein-coding nucleic acid (pDNA and mRNA) supplementation. The results of targeting strategies showed that the heart has been reported to a lesser degree, whereas no articles addressing kidney-targeting have been carried out. Moreover, the authors highlighted and discussed the importance to develop organ-specific nucleic acid delivery systems, the design of active-targeted carriers with high quality, good clinical translation, and large-scale manufacturing capacity.
In the field of brain delivery and anti-inflammatory therapy, Prof. Lammers and co-workers from the RWTH Aachen University, Aachen, Germany (https://doi.org/10.1007/s13346-024-01561-6), developed an advanced in vitro blood brain barrier (BBB) model to study the impact of sonopermeation on the delivery of the prototypic polymeric drug carrier pHPMA as a larger molecule and the small molecule antiviral drug ribavirin. The experiments were carried out under standard and inflammatory conditions and targeted and untargeted iRGD-microbubbles (MB) were used to induce temporally and spatially control the opening of the BBB. The BBB models was obtained by using human cerebral capillary endothelial cells and human placental pericytes, which are co-cultivated in transwell inserts and which present with proper transendothelial electrical resistance. The tumors, neurodegenerative diseases and CNS infections, tumor necrosis factor (TNF) was employed to induce inflammation in the BBB model. The authors demonstrated that RGD-coated MB bound to and permeabilized the inflamed endothelium-pericyte co-culture model, and potently improved Atto488-pHPMA and ribavirin delivery, thus providing a suitable model to study BBB inflammation and the relative mechanisms related to transport of bioactive molecules using nanoparticle.
Prof. Lammers and co-workers (https://doi.org/10.1007/s13346-023-01465-x) also studied tunable polymeric micelles for taxane and corticosteroid co-delivery for suppressing inflammation and infusion reactions, and thus, modulating the tumor microenvironment towards enhanced nano-chemotherapy delivery and efficacy. For this reason, amphiphilic mPEG-b-p(HPMAm-Bz) block copolymers of various molecular weights were synthesized and used to co-deliver paclitaxel (PTX) and dexamethasone (DEX) as a single and combined compounds in double-loaded micelles of different sizes. Both drugs were well loaded inside micelles and a slow release of PTX and fast release of DEX was observed from the micelles. The versatile properties of resulting micelles for the co-delivery of hydrophobic compounds demonstrated that hydrophobicity and molecular weight of drugs strongly affect their retention in micelles.
In another study, Prof. Sousa and co-workers from the National Center of Competence in Research Bio-Inspired Materials, University of Fribourg, Fribourg, Switzerland (https://doi.org/10.1007/s13346-023-01509-2) developed a novel nano-adjuvant composed of immune-stimulatory nanoparticles (ISN) loaded with interleukin (IL)-12 to decrease the IL-12 toxicity and enhance the immune response by macrophages and glioblastoma (GBM) cancer cells. In vitro experiments demonstrated that ISN substantially increases the production of pro-inflammatory cytokines in GBM cancer cells and macrophages. This data demonstrated the effective intracellular delivery of IL-12 by ISN, triggering alterations in the levels of pro-inflammatory cytokines at both transcriptional and protein expression levels, as well as highlighted the potential of the resulting nano-adjuvant in GBM therapy.
Furthermore, Prof. Choonara and co-workers from the University of University of the Witwatersrand, South Africa (https://doi.org/10.1007/s13346-024-01566-1) designed a thermos-responsive, nano-enabled vitreous substitute for the treatment of retinal diseases. Hyaluronic acid and a poloxamer were used for the synthesis of hydrogels, while poly(D, L-lactide-co-glycolide) acid nanoparticles, encapsulating triamcinolone acetonide (TA), were synthesized with a spherical morphology and mean diameter of ~ 153 nm. The hydrogels displayed in situ gel formation properties, and rheometric viscoelastic studies, showing that the unloaded and loaded hydrogels have modulus values similar to those of the natural vitreous at 37 °C. A minimal swelling with the relative equilibrium within 12 h for the unloaded hydrogel, and at 8 h for nanoparticles embedded hydrogels were carried out. Biodegradation in simulated vitreous humor with lysozyme showed < 20% degradation within nine weeks, and the resulting hydrogels, with and without nanoparticles, were biocompatible in vitro in mouse fibroblast and human retinal pigment epithelium cell lines. A pilot in vivo study in a New Zealand White rabbit model demonstrated the minimal toxicity with precise and controlled drug release, and the ocular TA levels were maintained within the therapeutic window for the 28-day investigation period.
Prof. Singh and co-workers from the Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney (https://doi.org/10.1007/s13346-024-01634-6) developed colon-targeted solid self-nanoemulsifying drug delivery systems of fisetin (FS) and studied the pharmacokinetic of payloads in rats. Results demonstrated that FS loaded in advanced nanocarriers showed a rapid absorption of FS in the animal models compared to free drug. Moreover, the resulting nanocarriers increased significantly the oral bioavailability of FS in the blood stream after administration.
Moreover, Prof. Meena and co-workers from the Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (https://doi.org/10.1007/s13346-024-01521-0) engineered and characterized pH-responsive polymer PLGA-coated magnetic silica nanoparticles (Fe3O4-SiO2-PLGA-PDA-PTX-siRNA NPs) co-loading paclitaxel (PTX) and siRNA against programmed cell death ligand-1 (PD-L1). The resulting nanoparticles were nanoparticles demonstrated pH-sensitive and provided a sustained drug release up to 10 days, while in vitro 4T1 cell line studies showed efficient cellular uptake, PD-L1 gene downregulation, and apoptosis. In vivo efficacy studies, carried out in a mice model, demonstrated a significant reduction of tumor growth following treatment with dual-Fe3O4-SiO2-PLGA-PDA-PTX-siRNA NPs as compared with monotherapy with Fe3O4-SiO2-PLGA-PDA-PTX NPs; while nanoparticles co-loaded with siRNA improved the CD8 + T cell-mediated cancer cell death.
In the field of topical drug delivery and infection diseases, Prof. Pemmaraju and co- workers from the National Institute of Pharmaceutical Education and Research, India (https://doi.org/10.1007/s13346-024-01594-x) developed nanoparticles to decrease acne and its related cutaneous infection. The authors synthesized near-infrared light-absorbing copper sulfide (CuS) nanoparticles loaded with a biomolecule, Glycyrrhizin (Ga), and studied their photothermal efficacy by using in vitro and in vivo models. Results demonstrated that Ga-CuS NPs generated localized hyperthermia in acne-causing bacteria and caused the complete growth inhibition of associated bacteria as well as significantly decreased the local inflammation. Moreover, the authors demonstrated that this innovative formulation could be suitable for application in cosmetic for the effective and minimally invasive management of acne-like conditions.
Prof. Nurunnabi and co-workers from the University of Texas El Paso (https://doi.org/10.1007/s13346-024-01551-8) provided an overview of RNA therapeutics as emerged and promising approach to potentially downregulate cytokine levels in cells responsible for the treatment of liver fibrosis. Different RNA-based therapeutics, such as mRNA, siRNA, miRNA, lncRNA, and oligonucleotides were studied to assess their efficacy in animal models and demonstrate their targeting and modulation on immune response and activation processes. Lipid nanoparticles, exosomes, nanocomplexes, micelles, and polymeric nanoparticles were studied to deliver therapeutic agents directly to specific biomarkers or cytokines within the fibrotic liver, as well as increase their effectiveness and reduce side effects. Moreover, this system review highlighted the importance of nanoparticles for the treatment of liver fibrosis and the development of effective and personalized treatment options in affected patients.
In the field of brain drug delivery, Prof. Celia from the University of Chieti– Pescara “G. d’Annunzio”, and Prof. Fresta from the University of Catanzaro “Magna Graecia” and co-workers (https://doi.org/10.1007/s13346-024-01556-3) studied liposome nanomedicine, with monosialic ganglioside type 1 (GM1), OX26 (an anti-transferrin receptor antibody), and CDP-choline (a neurotrophic drug) (CDP-choline/OX26Lip) and tested for post-ischemic therapeutic effect of CDP-choline in rat models. Results demonstrated that OX26 increased the accumulation of GM1-liposomes in the brain tissues and thus the efficacious of CDP-choline in rat brain ischemic stroke models, thus responding to a significant clinical need in the brain disease.
In the field of skin cancer treatment, Prof. Igartua and co-workers (https://doi.org/10.1007/s13346-024-01557-2) from the Institute of Health Carlos III, Madrid, Spain developed a personalized neoantigen peptide-based cancer vaccine by encapsulating patient derived melanoma neoantigens in polyethylenimine (PEI)-functionalised poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) and coated them with polyinosinic: polycytidylic acid (poly(I: C). PLGA NPs effectively stimulated dendritic cells (DCs) and lymphocytes and provided immune activation of competent cells. The results demonstrated that the developed vaccine had a high capacity to activate the immune system, efficiently maturing DCs to present the antigen of choice and promoting the activity of lymphocytes to exert their cytotoxic function, and they can represent a useful nanovaccine for melanoma treatment.
Prof. Andrés-Guerrero and co-workers from the Complutense University of Madrid (UCM) (https://doi.org/10.1007/s13346-024-01584-z) combined latanoprost (LAT)-loaded synthetic phosphatidylcholine liposomes with hyaluronic acid and the osmoprotectants betaine and leucine (LAT-HA-LIP) to extend the hypotensive effect of LAT while protecting the ocular surface. The resulting LAT-HA-LIP had optimal in vitro tolerance in human corneal and conjunctival epithelial cells, and did not alter ocular vision after instillation in albino male New Zeeland rabbit. Moreover, hypotensive studies demonstrated that, a single eye drop (24 h of instillation) of LAT-HA-LIP improved ocular bioavailability three times higher than commercial formulation, thus offering a potential therapeutic option for glaucoma treatment.
In another work, Prof. Santos and co-workers from the University Medical Center Groningen (https://doi.org/10.1007/s13346-024-01638-2) provided an overview of RNA-based technologies and demonstrated their potential across various clinical applications, particularly cancer therapy. Novel approaches were also studied to improve the targeting and bioavailability of RNA-based formulations, and thus, achieve appropriate therapeutic outcomes. Lipid nanoparticles (LNPs) were deeply studied and their advantages for RNAi delivery detailed discussed with many examples of therapeutic applications and treatment in cancer therapy, as well as their impact in personalized medicine and clinical applications.
Prof. Santos and co-workers (https://doi.org/10.1007/s13346-024-01649-z) also provided an overview of the application of natural compounds for the prevention and treatment of different cancers. The authors extensively reviewed the literature highlighting the most recent advances in the nanocarriers for natural compounds secreted from plants, bacteria, fungi, and marine organisms, as well as their role on cell signaling pathways for anticancer treatments. moreover, the clinical status and the main challenges regarding the natural compounds loaded in nanocarriers for clinical applications were also discussed.
Prof. Leclercq and Beloqui and co-workers from the Université Catholique de Louvain (https://doi.org/10.1007/s13346-024-01576-z) developed semaglutide-loaded lipid nanocapsules to treat metabolic dysfunction-associated steatotic liver disease (in mouse models and normalize glucose homeostasis and insulin resistance in dietary specific models. Semaglutide-loaded lipid nanocapsules had a positive trend on the metabolic syndrome and at reducing inflammation, mitigating the progression of the disease. Oral administration of the nanosystem was more efficient at preventing the progression of the disease to more severe states when compared to the administration of commercial product Rybelsus.
Prof. Peerson and co-workers from the University of Maryland School of Medicine (https://doi.org/10.1007/s13346-024-01632-8) developed ovalbumin (OVA) protein-poly(lactic-co-glycolic acid) (PLGA) conjugate NPs (acNP-OVA) to elucidate the impact of Ag loading on the induction of Th2 tolerance using a prophylactic and therapeutic OVA/ALUM-induced mouse model of allergic lung inflammation (ALI) in comparison to Ag-encapsulated PLGA NPs (NP(Ag)). The authors demonstrated that acNP-OVA formulations reduced OVA-specific IgE and inhibited Th2 cytokine secretions in an Ag loading-dependent manner when administered prophylactically and they did not affect OVA-specific IgE and Th2 cytokines in pre-sensitized mice. Moreover, the acNP-OVA with medium-to-low Ag loadings were well tolerated, while formulations with high Ag loadings, including NP(Ag) resulted in anaphylaxis.
Prof. Teesalu and co-workers from the University of Tartu (https://doi.org/10.1007/s13346-024-01670-2) developed PL3 peptide (AGRGRLVR),) derivatives that bind to neuropilin-1 (NRP-1) only after proteolytic processing by urokinase-type plasminogen activator (uPA), while maintaining binding to the other receptor of the peptide, the C-domain of tenascin-C (TNC-C). The authors demonstrated a rational design approach and screening of a uPA-treated peptide-phage library on the recombinant NRP-1, derivatives of the PL3 peptide capable of binding to NRP-1 only post-uPA processing were successfully identified. The in vitro cleavage, binding, and internalization assays, and in vivo biodistribution studies in orthotopic glioblastoma-bearing mice, confirmed the efficacy of two novel peptides, PL3uCendR and SKLG, which exhibited uPA-dependent binding to NRP-1, reducing off-target binding to healthy NRP-1-expressing tissues.
Overall, this special issue is expected to provide important background and new knowledge on the latest advances of nano- and bio- materials/nanomedicines, and their impact and significance in precision medicine by approaching specific and selective targeting strategies to boost nanoparticles from pre-clinical to clinical studies, and highlighting the significant impact of nanomedicine in biomedical and pharmaceutical applications.
We would like to express our sincere appreciation to all the authors who have contributed to this collection of articles. Our gratitude also goes to the journal’s Editor-in-Chief, staff, and reviewers, who have truly made the collection possible in the first place while ensuring the quality of all the papers included in this Special Issue. C. C. acknowledges financial support from the Ministero dell’Università e della Ricerca (MUR) [FAR 2018 (D56C18000780005), FAR 2019 (D54I19002790005)], and Overseas Visiting Fellow Program 2022, University of Shanghai, China. T. T. acknowledges financial support from Estonian Research Council (grants PRG230, PRG1788), EuronanomedIII projects ECM-CART and iNanoGun, and TRANSCAN3 project ReachGLIO. H. A. S. acknowledges financial support from UMCG Research Funds.
