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Competing Interests: None.

Nanomedicine plays an essential role in developing new therapies through novel drug delivery systems, diagnostic and imaging systems, vaccine development, antibacterial tools, and high-throughput screening. One of the most promising drug delivery systems are nanoparticles, which can be designed with various compositions, sizes, shapes, and surface modifications. These nanosystems have improved therapeutic profiles, increased bioavailability, and reduced the toxicity of the product they carry. However, the clinical translation of nanomedicines requires a thorough understanding of their properties to avoid problems with the most questioned aspect of nanosystems: safety. The particular physicochemical properties of nano-drugs lead to the need for additional safety, quality, and efficacy testing. Consequently, challenges arise during the physicochemical characterization, the production process, in vitro characterization, in vivo characterization, and the clinical stages of development of these biopharmaceuticals. The lack of a specific regulatory framework for nanoformulations has caused significant gaps in the requirements needed to be successful during their approval, especially with tests that demonstrate their safety and efficacy. Researchers face many difficulties in establishing evidence to extrapolate results from one level of development to another, for example, from an in vitro demonstration phase to an in vivo demonstration phase. Additional guidance is required to cover the particularities of this type of product, as some challenges in the regulatory framework do not allow for an accurate assessment of NPs with sufficient evidence of clinical success. This work aims to identify current regulatory issues during the implementation of nanoparticle assays and describe the major challenges that researchers have faced when exposing a new formulation. We further reflect on the current regulatory standards required for the approval of these biopharmaceuticals and the requirements demanded by the regulatory agencies. Our work will provide helpful information to improve the success of nanomedicines by compiling the challenges described in the literature that support the development of this novel encapsulation system. We propose a step-by-step approach through the different stages of the development of nanoformulations, from their design to the clinical stage, exemplifying the different challenges and the measures taken by the regulatory agencies to respond to these challenges.

Interferons (IFNs) are cytokines involved in the immune response that act on innate and adaptive immunity. These proteins are natural cell-signaling glycoproteins expressed in response to viral infections, tumors, and biological inducers and constitute the first line of defense of vertebrates against infectious agents. They have been marketed for more than 30 years with considerable impact on the global therapeutic protein market thanks to their diversity in terms of biological activities. They have been used as single agents or with combination treatment regimens, demonstrating promising clinical results, resulting in 22 different formulations approved by regulatory agencies. The 163 clinical trials with currently active IFNs reinforce their importance as therapeutics for human health. However, their application has presented difficulties due to the molecules' size, sensitivity to degradation, and rapid elimination from the bloodstream. For some years now, work has been underway to obtain new drug delivery systems to provide adequate therapeutic concentrations for these cytokines, decrease their toxicity and prolong their half-life in the circulation. Although different research groups have presented various formulations that encapsulate IFNs, to date, there is no formulation approved for use in humans. The current review exhibits an updated summary of all encapsulation forms presented in the scientific literature for IFN-α, IFN-ß, and IFN-γ, from the year 1996 to the year 2021, considering parameters such as: encapsulating matrix, route of administration, target, advantages, and disadvantages of each formulation.