The design and synthesis of new Nanomaterials applied for Bio-applications as Nanosensors of single molecule detection, Biosensors of biological events and controlled drug delivery nanoparticles are of high interest and impact in bioanalytical methodologies, clinical research and as well as from new areas of research as Nanophotonics, Biophotonics, and Nanomedicine. First, one of the higher challenges within all these research fields is how to transduce an analytical signal and transduce it from individual biological events or biomolecules. And at the same time secondly, it should be tracked biological event during the time by a selective response followed by a given therapy action depending of needs. In order to afford these challenges the control at the nanoscale incorporating different types of materials from hybrids Nanomaterials to Metamaterials for variable and biocompatible properties for targeted applications. Due to the high impact, if it is tuned these properties based on specific requirements new therapies within Precision medicine are open. For these reasons, in this short Review was exposed different strategies for Smart tunable Nanoarchitectures as Nanoplatforms for Bioconjugation to design Lab. On-particle and Drug delivery Nano-systems accompanied with Luminescent and Ultraluminescent properties based on Fluorescence Resonance Energy Transfer (FRET), Metal Enhanced Fluorescence (MEF), Enhanced Plasmonics (EP) coupled to MEF as well as FRET coupled to MEF applied for early diagnosis, biomolecular and DNA detection, Genomics, Gene therapies and Drug Delivery Systems by the application of synthetic and Bio-inspired Nanoarchitectures based on Hybrids Nanomaterials. By this manner advanced treatments in-situ or in vivo after stimulation by a smart bio-response were discussed.
hybrids nanomaterials, nanophotonics, biophotonics, nanomedicine
Design and controlled synthesis at the nanoscale of different types of nanoparticles composed as well by a large number of materials opened their application within different areas of Life Sciences  All these nanomaterials are from inorganic materials as metallic, semiconductors, quantum particles, and conductive; magnetic as well as organic materials from small molecules to polymeric nanomaterials with variable properties depending of their applications .
Within Life Sciences exist a huge number of challenges and needs; and for these reasons new areas of Research related with Optical Nanomaterials joined to Optics produced in the last years an exponential number of advanced Research publications accompanied with applications by the introductions of available products for Life Sciences studies, early diagnosis based on Imaging; and new treatments that it could contemplate Genomics for Precision Medicine. For all these applications the control of the classical light and non-classical light from new nanoarchitectures of Nano-emitters is of high impact and at the same time it is a Research Field as well.
Metal Enhanced Fluorescence (MEF) is a phenomena related with an increased emission of fluorescence emission produced by an enhanced absorption of the fluorophores in the near field of metallic surfaces where it is generated stronger electromagnetic fields that increase the higher electronic excited state [3-5]. This phenomenon could be collected from metallic surfaces as well as from nanoparticles.
Moreover in presence of multiple numbers of individual nanoparticles that interact producing enhanced electromagnetic fields between nanoparticles , known as Enhanced Plasmonics  (EP) can be coupled to MEF in order to collect increased molecular detection within the near field  Core-shell nanoparticles formed by metallic cores covered with variable silica shells for fluorescent modification showed enhanced properties related with the MEF phenomena accompanied with diminished photobleaching properties with high potential impact on Life Sciences. In addition supramolecular modifications showed enhanced detection based on non-covalent host-guest interactions coupled to a switched on-off MEF by a simple chemical reaction  with potential applications for Single Molecule Detection (SMD)  This proof of concept developed by us it could be extended to molecular tracking and host-guest complexes delivery in biological media by applications of antibodies recognition  as well. For these reasons the design and synthesis of different Nanoarchitectures based on Supramolecular chemistry [12,13] Organic chemistry joined to inorganic chemistry as well have potentials application within Biomaterials sciences for targeted applications due to their versatilities and tunable properties  as it was demonstrated by a controlled switched on-off variation of molecular fluorescence  that produced variable resolution with potential application within NanoImaging and Bioimaging. However, the challenge of the fluorescence control from molecular to Nanoscale levels still existing needs to be improved and enhanced the light generation.
Moreover, the importance of light collection as fluorescent emission it was showed from individual nucleic acids tracking by DNA fluorescent labelling by microfluidics coupled to Laser Fluorescence Microscopy Imaging analysis , as well as by single DNA strands detection with the application of fluorescent polymers  and intercalant agents .
All these mentioned Research fields can be applied for challenges related with Advanced issues within Genomics  and Precision Medicine [19,20], as for example for genotyping and targeted treatments, with potential application in epigenetics for non-canonical 3D DNA structures  as well. In addition to develop controlled sizes of particles at the nanoscale accompanied with smart responses it should be tuned each part of the Nanoarchitecture.
In this short Review was discussed the application of different Nanomaterials to develop hybrids Nanoparticles for Advanced Smart Ultraluminescent Multifunctional Nanoplatforms with applications within Biophotonics and Nanomedicine.
Smart hybrids nanocomposites
Different Nanoarchitectures by varying Nanomaterial composition could be obtained in order to be applied as Nanoplatforms of chemical functionalization for targeted applications. Moreover, these nanoparticles accompanied with variable composition and surface functionalization could act as responsive single dots that collect, transduce, enhance signals for tracking applications and produce specific actions depending of stimulations given by the environment. For the design of these Smart Nanomaterials should be combined different material properties coupling variable functions from each component added to finally obtain Meta-materials  and hybrids Nanoarchitectures . In addition to all these requirements another challenge should be added within Life Sciences related with the Bio-compatibility and toxicological issues  as well.
For Nanoplatforms design in colloidal dispersion it should be began from a template at the Nanoscale in order to add variable composition on it. By this manner variable templates could be applied going from inorganics Nanomaterials, as Aluminium , Indium , Cooper , Gold, Silver [27,28] with variable sizes and shapes; Organic materials, as Molecular spacers , lineal and branched Polymers  and Supramolecular systems [31,32] and Biological materials as antibodies , biomolecules , etc.. The deposition and chemical modification of the Nano-template will permit tuneable properties of the nanoparticle. For example bi-metallic Core-shell nanoparticles , metallic Core-shell polymeric silica nanoparticles , metallic Core-shell supramolecular nanoparticles , Polymeric Core-shell nanoparticles , etc.
These nanoparticles as Nanoplatforms accompanied with the right chemical modification showed to be Smart Nanosystems that produced variable responses depending of the Nanomaterial compositions as for example; fluorescence emission enhancement based on MEF , pH sensing based on the modification of the MEF signalling , fluorescent complex delivery tracked by enhanced fluorescence  Bioimaging with potential applications in Biodetection , drug delivery coupled to Imaging ; opening by this manner diverse applications as well as potential developments in many fields (Figure 1).
Figure 1. Scheme of Biocompatible and Ultraluminescent gold Core-shell nanoparticles (Au@SiO2-RhB) based on Metal Enhanced Fluorescence (MEF). Reprinted with permission from Ref 38 (Guillermo Bracamonte et al.). Copyright 2017 RSC Adv
Nanotechnological developments were produced in the last years at different levels accompanied with many discussions related with environmental implications, health risks, toxicology and ethical issues from the manipulation to the applications in real samples . But for the real application of Nanosensors, Biosensors and Nano-cargo for drug delivery in vivo, the first point to be taken into account is the Biocompatibility at first contact as well as at long term the bioaccumulation.
By this manner gold nanoparticles showed biocompatibility from small animals to non-human primates  and bio-applications , silver nanoparticles anti-microorganisms activity , biodegradable nanoparticles formed by variable synthetic and natural co-polymers based on hydrolysable organic functional groups .
And at this level the design by Bio-inspiration it should be applied and assayed in order to apply as for example lineal polymers of Polyethylene glycols (PEG) molecules of variable lengths to avoid Nanoaggregation with Bio-microstructures as cells and applied for nanoparticles synthesis . And then, these nanomaterials were evaluated as for example based on the analysis of their hydrophilicity and hydrophobic domains evaluating the Mitigation of Inflammatory Immune Responses . By this manner, it could be highlighted the Cyclodextrins supramolecular structures formed by glucose (cyclic oligosaccharides), that they were applied for conducting the first in-human phase I clinical trial involving the systemic administration of siRNA to patients with solid cancers using a targeted, nanoparticle delivery system .
So, for Lab-on particles developments, Nano-cargo for drug delivery, Ultraluminescent Nanoplatforms for Bioimaging; and surface Nanoparticle Bioconjugations; it should be contemplated many Biocompatibilities issues for in vivo applications that add an additional challenge and Research work.
In the last years the most important discussion about Medicine came from Cellular Biology, Biomolecular studies and Genomics Research  from where it was generated many concepts and new ideas towards targeted and specific treatments . And within this field the higher impact came from human genome studies ; phenotypes and Epigenetics , due to that all the modifications produced different biomolecular and structural variations accompanied with variable biological compositions and functionalities as well. In this way, it should be highlighted based on the genomic knowledge a gene therapy by the embryonic cell modifications with CRISP (clustered regularly interspaced short palindromic repeats) . This technique was based on enzymatic scissors that permitted to modify the genetic code by the correction of β-thalassemia mutant related with hemoglobin production disorders . Moreover, it should be highlighted as well the importance of the recently application of gold nanoparticles as Nanoplatforms and Nano-carriers for targeted Delivery of CRISPR-Cas9 Therapeutics .
By this way, many other examples could be cited; but it is mentioned, due their importance, the gene related with the intolerance of the lactose . This gene was produced by random mutations occurred in regions upstream of the LCT gene depending of variable phenotypes patterns depending of regions of all around the world. By this manner, an extra challenge could be added for faster analysis and early diagnosis based on new and faster Bioimaging assays .
Biological signalling tracking by enhanced fluorescence methodologies
From Physics, Optics, Nanophotonics and Biodetection Research studies were afforded many Research challenges of Biology as internal molecular cells signals as light emissions that opened new Research fields as Biophotonics.
Fluorescence Resonance Energy Transfer  (FRET) have already developed and studied for molecular sensing and applied for Biophotonics  applied to biological signal tracking. As it is known FRET by individual molecules interactions showed a short length effect related with energy transfer. In addition, the overlapping of donor-acceptor spectroscopical characteristics was required, as well as the quantum yields of both emitters to low signals recording. In order to overcome these low signalling it should be highlighted the FRET coupled to enhanced fluorescence techniques as Metal Enhanced Fluorescence (MEF) by Multi-layered silver Core-shell nanoparticles  with the incorporation of a fluorescent positively charged Polymer and silica shell; as well as between inter-nanoparticle dimmers linked by complementary DNA strands  developed by Boudreau and Lakowicz et al. respectively; where the short distance at the nanoscale should be accurately controlled . However, from Nanophotonics new studies based on confined molecules showed as well as long distances energy transfer effect  between electromagnetic couplings of them with potential Bio-applications.
All these studies demonstrated the versatility and application of these phenomena between individual molecules positioned at the right distance to transduce fluorescence energy signals. For these reasons FRET was applied by different techniques, as for example microscopy imaging of live cells for protein localizations , by Cytometry it was even studied molecular interaction within cells  and by Fluorescence Lifetime Imaging Microscopy (FLIM)  it was arrived to studies of protein-protein interactions. At the same time, in order to understand limit of detections, the importance of statistics and data collection related with non-radiative pathways via FRET from individual molecules are very important too . By this manner there are still existing challenges and needs to be afforded due to the low concentrations present in nature for in vivo applications for Single Molecule Detection (SMD)  techniques. As for example, it could be mentioned from Bacterial interne molecular signalling  and special requirements and challenges for sensing in vivo and real samples with Nanosensors .
Moreover, it should be mentioned the high impact based on advances of new Photonic Nano-materials based on biomolecules as DNA and RNA joined to FRET phenomena  with potential real applications within genomics . So, depending of the research directions of the design of new Nanomaterials will be as well the impact on the availability of new tools for Nanomedicine and Research .
Metal enhanced fluorescence (MEF), FRET and coupled methodologies
The Ultra luminescent properties are based on a plasmonic effect named Metal Enhanced Fluorescence (MEF). Metal enhanced fluorescence (MEF) is a plasmonic effect that enhances the emission fluorescence of a substrate placed at a given distance from a metallic surface . The MEF effect depends of the distance of the fluorophore from the metallic surface due to the electromagnetic field intensity decays exponentially (1/r3) affecting by this manner drastically the fluorophore excitation . For this reason in order to evaluate this parameter there are many studies developed using polymeric spacers as silica. In these Nanoarchitectures, the fluorophore is covalent bonded and the concentration can be controlled for maximal enhancements. These studies are in progress over surfaces  and colloidal dispersions , depending of the Nanoarchitecture design and applications. The main parameters to be controlled for optimal enhancements are the following: a) plasmonic complementarity of the Nanoparticle with the fluorophore, b) the distance and position of the dipolar momentum of the fluorophore from the metallic surface, c) the concentration of the fluorophore and d) the Nano aggregation state. Each of these parameters should be studied for optimal properties depending of the targeted property and application.
About Medical Imaging based on fluorescent techniques can be mentioned fluorescence molecular tomography, where based on this technique many developments were done in order to generate images in vivo using specific fluorophores  In addition from the viewpoint of NanoImaging with potential application, there are more developments done for cancer detection , cell targeting , and membrane characterization ; where the resolution it is an important factor to control and tune depending of the nanoscale of application that can be from a few molecules aggregates  to membranes and higher structures . For this reason the relevance of the control of the nanostructure size and luminescent properties it is an important factor in order to design multifunctional nanoparticles applied to diagnostics and Nanomedicine based on Nano Imaging in vivo, where it is essential a) targeting, b) detection, c) tracking, c) stability of the signal, d) and activation of additional switchable function depending of the environment. So, as it was discussed the classical, non-classical and bio-light or luminescence generated and transduced was highly dependent of inter-emitter distances as well. For all these reasons there are large number different Research fields focussed on Optics and resolution imaging, Biostructures detection and characterisation, and accurate synthesis at the Nano-scale of variable material compositions.
Nanophotonics for biophotonics and early diagnosis
Nanophotonics Research based on Nanomaterial in colloidal dispersion as well as deposed over modified surfaces, focussed on Bio-applications are in current development affording different challenges of high impact that contemplated from small Bio-molecules tracking, DNA, Cells, Bacteria and Biostructures detections for early diagnosis. In addition the detection should be accompanied with advanced and personalized treatments with tracking at long terms for optimal results. By this manner these fields are on the frontiers of chemical, drugs and personalized Nanomedicine.
From these fields not only it will generated detection and tracking of Biological events; but as well it will be contemplated a total control of all the environment of study in order to regulate the normal functionalization or even improve it for specific objectives of higher level that will produce, activate and modify the original bio-functions.
In this way, based on the Nanoscale and MEF control many publications were reported recently contemplating variable Nanotechnological applications  by the design and synthesis of Ultraluminescent Nanoplatforms of Core-shell nanoparticles for small biomolecules detection , Multi layered silver Core-shell nanoparticles for enhanced detection of DNA , that generated impact on new Research fields as for example Metal-Enhanced Fluorescence in Plasmonic Waveguides by Boudreau et al. , and smart responsive low volume conical 96 well plates for enhanced Fluorescence applications, accompanied with MEF enhancements of 100, with Patent pending, based on surface modifications by Geddes et al.  (Figure 2).
Figure 2. Fluorescent multilayer core-shell NPs architecture for DNA detection in three steps: 1) target-ready NPs are prepared by complexing ssDNA probe-grafted NPs with a fluorescent polymer transducer; 2) hybridization of target DNA with ssDNA probes activates the polymer transducer as energy donor toward dye-doped silica shell and excitation at 410 nm generates fluorescence emission by acceptor molecules at 550 nm. Reprinted with permission from Ref 85 (Denis Boudreau et al.). Copyright 2014 Hindawi. Advances in Chemistry
In addition, the detection of different types of bacteria is highly required in Bioanalytical Chemistry, Clinical Chemistry, and environmental chemistry due to their high impact in different fields as Biodetection for different reasons. By this manner it was applied Ultraluminescent and biocompatible gold Core-shell nanoparticles previously developed by Bracamonte et al., based on MEF , for individual Escherichia Coli bacteria labelling and detection by Laser Fluorescence Microscopy  (Figure 3).
Figure 3. Biodetection of individual Escherichia coli bacterium: a) Fluorescence microscopy of individual
Escherichia coli bacteria labelled with luminescent gold-core shell nanoparticles (image edited with green colour LUT). b) Image edited by two-colour analysis with red-green LUT. The insets are amplification of luminescent Core-shell Nanoparticles indicated with white circles (Intensities x102). Reprinted with permission from Ref 88 (Guillermo Bracamonte et al.). Copyright 2018 J. of Nanophotonics
Moreover, as it was previously discussed within Biophotonics is highly desired individual biomolecules detection for early diagnosis. In this way, it should be mentioned Single Molecule Detection (SMD) Nanoplatforms developed by Bracamonte et al.  based on MEF (Figure 4) and Enhanced Plasmonics coupled to MEF in progress as well. Further Research work it should be done in order to improve and apply these types of Nanoarchitectures Bioconjugated with antibodies for In Flow methodologies coupled to different Optical techniques; and in-vivo biomolecular tracking by Laser Fluorescence Microscopy as well.
Figure 4. Single Molecule Detection (SMD) Nanoplatform: a) Schematic representation of Gold nanoparticles grafted with β CD. b) Molecular recognition event based on a supramolecular interaction of βCD and Plasmonic interaction. c) Laser Fluorescence Microscopy Imaging of aggregated nanoparticles. Inset image: Individual nanoparticles detection. Reprinted with permission from Ref 89 (Guillermo Bracamonte et al.). Copyright 2018 J. of Nanophotonics
Nanomedicine based of bioimaging, genomics and drug delivery systems
New treatments related with different health problems as well as improvements in the functionalities of many metabolic pathways by a targeted Nano-cargo drug delivery systems that produce a response just only against media modifications is and it will be a challenge to overcome. In addition early diagnosis of special needs depending of individual constitutions open the Genomics knowledge that it is a high impact field from all the constitutive matter of humans is generated; and after the decoding of the whole genome its looks like it should be applied. However, still existing needs and challenges in many other fields from where it will be taken knowledge to be part of early diagnosis and specific treatment required.
As example it could be described, a label free DNA Biosensing based on a multilayered fluorescent nanocomposite and a cationic polymer that interact specifically with the DNA strands showing an enhanced quantum yield in presence of the double strands developed by Boudreau et al.. This activated energy of the fluorescent polymer after the complementary DNA interaction was coupled to MEF by a silver Core-shell nanoparticle as energy acceptor that produced bright and strong spot within in flow methodology coupled to Laser Fluorescence detection . Then, this proof of concept, was applied to the Direct molecular detection of SRY gene from unamplified genomic DNA by metal-enhanced fluorescence and FRET  (Figure 5) and validated in real samples of blood  as well. This example was applied to the gen SRY but it could be developed to another gens depending of needs.
Figure 5. Genotyping based on Imaging Flow Cytometry (IFC): Fluorescence NanoImaging recorded at the nominal emission wavelength of the eosin emitter as energy acceptor of (A) target ready Nanoparticles without complementary targets; and of (B) target Nanoparticles with the addition of complementary targeted DNA strands. Reprinted with permission from Ref 90 (Denis Boudreau et al.). Copyright 2011 ACS Nano
In addition, from Metabolomics based on the gene expression as well it is required the detection of different biomolecules as proteins. Within this field it could be mentioned the development done by Koenig et al. for peptides and proteins detection based on a Luminescent vesicle formed by fluorescent energy acceptors incorporated near protein recogniser sites given by supramolecular systems  as well. Then, this proof of concept was applied to thrombin  detection in blood real samples.
Moreover, as it was mentioned previously to the Biocompatibility of the Nanomaterials it should be tuned specific properties for tracking applications. For example Biocompatible Ultra luminescent gold Core-shell Nanoplatforms for multifunctional applications developed by Bracamonte et al.  and applied to Ultraluminescent Escherichia Coli Biolabelling ; it could be mentioned.Then, they were tuned at different sizes and by this manner variable Nano-resolution were obtained; that produced detail of bacteria structures as well. From these controlled luminescence at the nanoscale potential applications it could be developed for non-canonical forms of DNA imaging and by this manner new approaches of Nanoplasmonics materials for Biosensing and Enhanced Light-Matter Interactions .
After the early diagnosis, where the time and costs are fundamental in order to expand their application it should be applied targeted treatments; and there it should be mentioned all the targeted Nanoarchitectures cargo for drug delivery applications. To this functionality it should be added extra functionalities and by this manner design and synthesis of Multifunctional Nanocomposites.
Cargo delivery Nano-systems of drugs, biomolecules, DNA and RNA, enzymes for controlled dosification depending of need and specific treatments should be developed in the next years. Enzymatic protection by Nano-carriers as for example CRISPR, controlled delivery of SiRNA, antibiotic administrations, and enhanced luminescent tracking of Cargo Nanoparticles and controlled drug delivery accompanied by Imaging methodologies developments, and joined to Optical activation as well. It could be mentioned as for example, from recently published articles, a smart responsive insulin administration against glucose , self-assembled gold nanoclusters for Bright Fluorescence Imaging and Enhanced Drug Delivery combining plasmonic and polymeric properties, only modifying the pH of the medium  Cargo Nanoparticles tracking , and quantifying drug uptake in skin by fluorescence . And just to finish it should be highlighted the impact of Optical developments in these Research fields on the previous issues discussed, as for example Fluorescence Molecular Tomography (FMT) , as well as with non-invasive signalling tracking for Neuro-photonics, Epigenetics and Bioimaging  (Figure 6).
Figure 6. Schematic representation of Cargo loaded nanoparticles for tracking and drug delivery applications.
Many challenges should be taken into account within this field from different points of view in order to develop new Nanomaterials joining multidisciplinary knowledge. By this manner it should be highlighted the control of the size at the Nanoscale accompanied with higher intensities from reduced surfaces for Nanoparticle tracking and improved Biostructures resolution. Developments of Nanoplatforms for Single Molecule Detection (SMD); coupled to In Flow methodologies and Optical detection based on Imaging.
For Advanced Nanomedicine, to prevent health problems as well as to improve the healthy population, by Precise and personalized treatments it is essential to develop Nano-platforms for Genomics and Epigenetics diagnosis based on Biophotonics and Bioimaging. And at this point it should be highlighted the early detection of gene expression based non-canonical 3D forms and Epigenetics.
Moreover, for in-vivo applications Biocompatible Hybrids Nanomaterials with tunable properties for drug loading and smart responsive controlled delivery are vital for Cargo Nanoarchitectures for enzyme, and Biomolecule targeted administration applied for specific treatments. In addition, Multifunctional nanoparticles and Multi-layered nanoparticles in order to afford diverse targeted functions accompanied with smart responsive actions at the different steps of the treatments are highly desired. And, it should be highlighted as well the application of Nanoarchitectures for improve health and well-being as prevention for the healthy population as well accompanied with physical activities that it could be even being applied within Biopharma and Nutraceutics products.
We would like to gratefully acknowledge the different Grants received in order to accomplish the Research work in progress of the authors in this field, CONICET, Consejo Nacional de Investigaciones Científicas y Técnicas (National Research Council of Argentine); ANPCyT, Agencia Nacional de Promoción Científica y Tecnológica (National Agency of Scientific and Technology Promotion of Argentine); and especially to SECyT (Secretary of Science and Technology from the National University of Cordoba (UNC), Argentina, for awarding us the extension of the Grant for Young Researchers at INFIQC.
Moreover, especially thanks to Professor Denis Boudreau from Département de chimie and Centre d’optique, photonique et laser (COPL), Québec, Canada, for the Research Collaboration in progress; as well as specially thanks to all the Canadian Grants that permit it.
Finally specially thanks to Lucia V. Bracamonte and Rosalia F. Bracamonte for the English revision.
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