**1. Polymeric Nanofibers in Biomedicine: General Overview**

The improvement of chemotherapeutic treatments in cancer patients is seriously limited by the difficulty of increasing the ability of drugs to specifically target tumor cells, thus reducing their toxicity in healthy cells. However, these antitumor molecules cannot increase their therapeutic response, which leads to poor prognosis and results in serious health problems, due to the prevalence of these several pathologies. Consequently, further research is needed to find new therapeutic approaches that improve the prognosis of patients affected by several types of cancers, thus decreasing the possible mortality rate. In this context, new strategies are appearing concerning the development of systems with the capability to encapsulate chemotherapeutic drugs and act as vehicles to be delivered in a specific area in a higher extension, thus avoiding the previously mentioned limitations and improving their efficiency, specifically in tumor cells [1,2]. According to the data from the World Health Organization, cancer caused 9.6 million deaths in 2018, and is one of the leading causes of death worldwide. The most common tumors are lung, breast and colorectal cancer [3]. For this reason, it is important to develop new nanoformulations that allow the improvement of cancer treatments and therefore the survival of these patients.

In general, drug delivery systems are nanostructures that can be loaded with small molecules or macromolecules, thus acting as vehicles of specific compounds to be used in a pharmaceutical administration process. Nowadays they represent one of the most promising challenges in the improvements of biomedical investigations [4]. Such materials are able to transport a chemotherapeutic molecule to a desired area, thus increasing the drug concentration, to be subsequently released in a controlled manner. Among a great number of nanoformulations, such as liposomes [5], micelles [6], Pickering emulsions [7], dendrimers [8] or nanoemulsions [9], polymeric nanoparticles (NPs) have been extensively reported as drug delivery systems to be applied in, for example, the chemotherapeutic treatment of solid tumors [9]. These NPs can be composed by synthetic polymers such as polylactic acid (PLA), poly lactic-co-glycolic acid (PLGA) or polyethylene glycol (PEG) [10,11], which in principle can be administered as colloidal systems and dispersed in a solution by means of intravenous administration. However, during the last years, apart from colloidal structures, polymeric nanofibers (NFs) have been reported as a scaffold with the ability to encapsulate antitumor drugs for biomedical investigations, including drug delivery and cancer treatments [12,13]. Among various techniques available for NFs fabrication, electrospinning is simple and produces NFs with high interconnected pores in the nanoscale range [14], having also a large surface area-to-volume ratio, high interfiber porosity, low hindrance for mass transfer, flexible handling, adjustable morphology, and high mechanical strength, which make NFs useful as therapeutic patches or mats for biomedical applications [15,16], indeed they are used in the fabrication of non-woven fibers with diameters ranging from a few nanometers to microns.

In the electrospun technique, when a strong electrostatic field is applied to a polymer solution held in a syringe, the pendent droplet of the polymer solution is deformed into a Taylor cone [17]. When the electric force overcomes the surface tension of the droplet, one or multiple charged jets are ejected from the tip of the droplet. As the jet moves towards a collecting metal screen, the solvent evaporates, and a nonwoven fabric mat is formed on the screen. This technique is able to fabricate fibers with diameter in the order of nanometers. During the last years, by using this technique, a great number of polymers have been used for the generation of biocompatible NFs scaffolds [18]. Biodegradable synthetic polymers such as PCL or PLGA, as well PEG and PLA can be used as substrates for the fabrication of NFs by using electrospun approaches [19]. Importantly, during the last few years, other types of polymers with stimuli-responsive behavior have been investigated as NFs scaffolds [20]. Two examples are poly(N-Isopropylacrylamide) (pNIPAM) and poly(4-vinylpyridine), which are the most investigated thermo- and pH-responsive polymers, respectively. By using this technique, the fiber diameter can be modulated by several polymer solution properties as viscosity, elasticity, polymer concentration and conductivity, the electric field strength, the distance between the injector and the metal collector, or other external parameters as temperature and humidity. Importantly, these NFs can incorporate and accumulate chemotherapeutic molecules by means of two main approaches [21]; (i) Blend electrospinning, which is based on mixing a drug with a polymeric solution prior to electrospinning process or (ii) Coaxial electrospinning, which is basically a simultaneous co-spinning of two polymeric liquids. The general system for this "core/shell" electrospinning is based on two needles, structured in a coaxial manner Indeed, drugs can be incorporated into the NFs through

physical adsorption (involving electrostatic interactions) [22] or covalent bond [23], as well as the aforementioned co-axial electrospinning or mixing with the polymer solution. By applying some of the previously mentioned approaches, electrospinning also offers the possibility to fabricate hybrid composites NFs. These composites structures are produced by the incorporation of other systems with specific properties into the polymeric NFs as CNTs, magnetic nanoparticles or metal nanoparticles. Among several reported reviews concerning the fabrication of polymeric NFs by electrospinning for drug delivery purposes [24–26], the principal novelty of this review is that we include recent advances for the fabrication and application of polymeric NFs by electrospinning not only focused in polymeric NFs. We also include recent investigation in 3 major items: (i) the incorporation of particles as nanocarriers into the NFs (vesicles, micelles or silica particles), which are able to increase drug accumulations, (ii) the fabrication of polymeric NFs with the capability to respond to external environments, and (iii) the generation of hybrid systems structured as polymeric NFs containing CNTs, magnetic and gold nanoparticles for hyperthermia applicability.
