COVID-19 cooling: Nanostrategies targeting cytokine storm for controlling severe and critical symptoms.

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to wreak havoc worldwide, the "Cytokine Storm" (CS, also known as the inflammatory storm) or Cytokine Release Syndrome has reemerged in the public consciousness. CS is a significant contributor to the deterioration of infected individuals. Therefore, CS control is of great significance for the treatment of critically ill patients and the reduction of mortality rates. With the occurrence of variants, concerns regarding the efficacy of vaccines and antiviral drugs with a broad spectrum have grown. We should make an effort to modernize treatment strategies to address the challenges posed by mutations. Thus, in addition to the requirement for additional clinical data to monitor the long-term effects of vaccines and broad-spectrum antiviral drugs, we can use CS as an entry point and therapeutic target to alleviate the severity of the disease in patients. To effectively combat the mutation, new technologies for neutralizing or controlling CS must be developed. In recent years, nanotechnology has been widely applied in the biomedical field, opening up a plethora of opportunities for CS. Here, we put forward the view of cytokine storm as a therapeutic target can be used to treat critically ill patients by expounding the relationship between coronavirus disease 2019 (COVID-19) and CS and the mechanisms associated with CS. We pay special attention to the representative strategies of nanomaterials in current neutral and CS research, as well as their potential chemical design and principles. We hope that the nanostrategies described in this review provide attractive treatment options for severe and critical COVID-19 caused by CS.

Custom-Design of Multi-Stimuli-Responsive Degradable Silica Nanoparticles for Advanced Cancer-Specific Chemotherapy.

Chemotherapy is crucial in oncology for combating malignant tumors but often encounters obatacles such as severe adverse effects, drug resistance, and biocompatibility issues. The advantages of degradable silica nanoparticles in tumor diagnosis and treatment lie in their ability to target drug delivery, minimizing toxicity to normal tissues while enhancing therapeutic efficacy. Moreover, their responsiveness to both endogenous and exogenous stimuli opens up new possibilities for integrating multiple treatment modalities. This review scrutinizes the burgeoning utility of degradable silica nanoparticles in combination with chemotherapy and other treatment modalities. Commencing the elucidation of degradable silica synthesis and degradation mechanisms, emphasis is placed on the responsiveness of these materials to endogenous (e.g., pH, redox reactions, hypoxia, and enzymes) and exogenous stimuli (e.g., light and high-intensity focused ultrasound). Moreover, this exploration delves into strategies harnessing degradable silica nanoparticles in chemotherapy alone, coupled with radiotherapy, photothermal therapy, photodynamic therapy, gas therapy, immunotherapy, starvation therapy, and chemodynamic therapy, elucidating multimodal synergies. Concluding with an assessment of advances, challenges, and constraints in oncology, despite hurdles, future investigations are anticipated to augment the role of degradable silica in cancer therapy. These insights can serve as a compass for devising more efficacious combined tumor treatment strategies.

Recent Advances of Light/Hypoxia-Responsive Azobenzene in Nanomedicine Design.

Azobenzene (Azo) and its derivatives are versatile stimuli-responsive molecules. Their reversible photoisomerization and susceptibility to reduction-mediated cleavage make them valuable for various biomedical applications. Upon exposure to the UV light, Azo units undergo a thermodynamically stable trans-to-cis transition, which can be reversed by heating in the dark or irradiation with visible light. Additionally, the N=N bonds in azobenzenes can be cleaved under hypoxic conditions by azoreductase, making azobenzenes useful as hypoxia-responsive linkers. The integration of azobenzenes into nanomedicines holds promise for enhancing therapeutic efficacy, particularly in tumor targeting and controllable drug release. In this Concept paper, recent advances in the design and applications of azobenzene-based nanomedicines are updated, and future development opportunities are also summarized.

TRPA1-Related Diseases and Applications of Nanotherapy.

Transient receptor potential (TRP) channels, first identified in Drosophila in 1969, are multifunctional ion channels expressed in various cell types. Structurally, TRP channels consist of six membrane segments and are classified into seven subfamilies. Transient receptor potential ankyrin 1 (TRPA1), the first member of the TRPA family, is a calcium ion affinity non-selective cation channel involved in sensory transduction and responds to odors, tastes, and chemicals. It also regulates temperature and responses to stimuli. Recent studies have linked TRPA1 to several disorders, including chronic pain, inflammatory diseases, allergies, and respiratory problems, owing to its activation by environmental toxins. Mutations in TRPA1 can affect the sensory nerves and microvasculature, potentially causing nerve pain and vascular problems. Understanding the function of TRPA1 is important for the development of treatments for these diseases. Recent developments in nanomedicines that target various ion channels, including TRPA1, have had a significant impact on disease treatment, providing innovative alternatives to traditional disease treatments by overcoming various adverse effects.

Innovative Nanoparticulate Strategies in Colon Cancer Treatment: A Paradigm Shift.

As a major public health issue, colorectal cancer causes 9.4% of total cancer-related deaths and comprises 10% of new cancer diagnoses worldwide. In the year 2023, an estimated 153,020 people are expected to receive an identification of colorectal cancer (CRC), resulting in roughly 52,550 fatalities anticipated as a result of this illness. Among those impacted, approximately 19,550 cases and 3750 deaths are projected to occur in individuals under the age of 50. Irinotecan (IRN) is a compound derived from the chemical structure of camptothecin, a compound known for its action in inhibiting DNA topoisomerase I. It is employed in the treatment strategy for CRC therapies. Comprehensive in vivo and in vitro studies have robustly substantiated the anticancer efficacy of these compounds against colon cancer cell lines. Blending irinotecan in conjunction with other therapeutic cancer agents such as oxaliplatin, imiquimod, and 5 fluorouracil enhanced cytotoxicity and improved chemotherapeutic efficacy. Nevertheless, it is linked to certain serious complications and side effects. Utilizing nano-formulated prodrugs within "all-in-one" carrier-free self-assemblies presents an effective method to modify the pharmacokinetics and safety portfolio of cytotoxic chemotherapeutics. This review focuses on elucidating the mechanism of action, exploring synergistic effects, and innovating novel delivery approaches to enhance the therapeutic efficacy of irinotecan.

Inflammation targeted nanomedicines: Patents and applications in cancer therapy.

Evident role of inflammation in cancer development and progression prompted the application of anti-inflammatory medications as a therapeutic strategy. The major bottleneck for the anti-inflammatory drugs is targeted delivery to the cancerous cell. Nanotechnology has provided safe and effective way for targeted cancer therapy. However, the complex and heterogeneous traits of cancer, incomplete information on fate and behavior of nanomedicines in human body, and lack of large-scale commercial production have slowed down the pace of nanomedicines development. To shift the paradigm from conventional cancer therapeutics to anti-inflammatory nano-therapeutics, thorough understanding of the strategies, progress, success, challenges and future perspectives are needed. The present review highlights all these aspects in addition to innovations patented on them. In fact, patent plays a vital role in protection of innovations, and further translation of lab-scale outcomes into bedside medications. Thus, the review introspects and recognizes the glitches in successful clinical translation of anti-inflammatory nanomedicines.

Targeted co-delivery of PD-L1 monoclonal antibody and sorafenib to circulating tumor cells via platelet-functionalized nanocarriers.

BACKGROUND: Circulating tumor cells (CTCs) can adsorb and activate platelets to form a microthrombus protective barrier around them, so that therapeutic drugs and immune cells cannot effectively kill CTCs. The platelet membrane (PM) bionic carrying drug system has the powerful ability of immune escape, and can circulate in the blood for a long time. MATERIALS AND METHODS: we developed platelet membrane coated nanoparticles (PM HMSNs) to improve the precise delivery of drugs to tumor sites and to achieve more effective immunotherapy combined with chemotherapy strategy. RESULTS: Successfully prepared aPD-L1-PM-SO@HMSNs particles, whose diameter is 95-130 nm and presenting the same surface protein as PM. Laser confocal microscopy and flow cytometry experimental results showed that the fluorescence intensity of aPD-L1-PM-SO@HMSNs was greater than SO@HMSNs that are not coated by PM. Biodistribution studies in H22 tumor-bearing mice showed that due to the combined action of the active targeting effect and the EPR effect, the high accumulation of aPD-L1-PM-SO@HMSNs in the local tumor was more effective in inhibiting tumor growth than other groups of therapeutic agents. CONCLUSION: Platelet membrane biomimetic nanoparticles have a good targeted therapeutic effect, which can effectively avoid immune clearance and have little side effects. It provides a new direction and theoretical basis for further research on targeted therapy of CTCs in liver cancer.

Chimeric Peptide-Engineered Self-Delivery Nanomedicine for Photodynamic-Triggered Breast Cancer Immunotherapy by Macrophage Polarization.

A systemic treatment strategy is urgently demanded to suppress the rapid growth and easy metastasis characteristics of breast cancer. In this work, a chimeric peptide-engineered self-delivery nanomedicine (designated as ChiP-CeR) for photodynamic-triggered breast cancer immunotherapy by macrophage polarization. Among these, ChiP-CeR is composed of the photosensitizer of chlorine e6 (Ce6) and the TLR7/8 agonist of lmiquimod (R837), which is further modified with tumor matrix targeting peptide (Fmoc-K(Fmoc)-PEG8 -CREKA. ChiP-CeR is preferred to actively accumulate at the tumor site via specific recognition of fibronectin, which can eradicate primary tumor growth through photodynamic therapy (PDT). Meanwhile, the destruction of primary tumors would trigger immunogenic cell death (ICD) effects to release high-mobility group box-1(HMGB1) and expose calreticulin (CRT). Moreover, ChiP-CeR can also polarize M2-type tumor-associated macrophages (TAMs) into M1-type TAMs, which can activate T cell antitumor immunity in combination with ICD. Overall, ChiP-CeR possesses superior antitumor effects against primary and lung metastatic tumors, which provide an applicable nanomedicine and a feasible strategy for the systemic management of metastatic breast cancer.

Polysaccharide-Based Stimulus-Responsive Nanomedicines for Combination Cancer Immunotherapy.

Cancer immunotherapy is a promising antitumor approach, whereas nontherapeutic side effects, tumor microenvironment (TME) intricacy, and low tumor immunogenicity limit its therapeutic efficacy. In recent years, combination immunotherapy with other therapies has been proven to considerably increase antitumor efficacy. However, achieving codelivery of the drugs to the tumor site remains a major challenge. Stimulus-responsive nanodelivery systems show controlled drug delivery and precise drug release. Polysaccharides, a family of potential biomaterials, are widely used in the development of stimulus-responsive nanomedicines due to their unique physicochemical properties, biocompatibility, and modifiability. Here, the antitumor activity of polysaccharides and several combined immunotherapy strategies (e.g., immunotherapy combined with chemotherapy, photodynamic therapy, or photothermal therapy) are summarized. More importantly, the recent progress of polysaccharide-based stimulus-responsive nanomedicines for combination cancer immunotherapy is discussed, with the focus on construction of nanomedicine, targeted delivery, drug release, and enhanced antitumor effects. Finally, the limitations and application prospects of this new field are discussed.

Advance in Nanomedicine for Improving Mucosal Penetration and Effective Therapy of Cervical Cancer.

Insufficient intratumor drug distribution and serious adverse effects are often associated with systemic chemotherapy for cervical cancer. Considering the location of cervical cancer, access to the cervix through the vagina may provide an alternative administration route for high drug amounts at the tumor site, minimal systemic exposure as well as convenience of non-invasive self-medication. Enormous progress has been made in nanomedicine to improve mucosal penetration and enhance the effectiveness of therapy for cervical cancer. This review article first introduce the physiological state of cervicovaginal cavity and the characteristics of intravaginal environment in cervical cancers. Based on introduction to the physiological state of cervicovaginal cavity and the characteristics of intravaginal environment in cervical cancers, both "first mucus-adhering then mucosal penetration" and "first mucus-penetrating then mucosal penetration" strategies are discussed with respect to mechanism, application condition, and examples. Finally, existing challenges and future directions are envisioned in the rational design, facile synthesis, and comprehensive utilization of nanomedicine for local therapy of cervical cancer. This review is expected to provide useful reference information for future research on nanomedicine for intravaginally administered formulations for topical treatment of cervical cancer.

CaO2nanomedicines: a review of their emerging roles in cancer therapy.

Metal peroxide-based nanomedicines have emerged as promising theranostic agents for cancer due to their multifunctional properties, including the generation of bioactive small molecules such as metal ions, H2O2, O2, and OH-. Among these metal peroxides, calcium peroxide (CaO2) nanomedicines have attracted significant attention due to their facile synthesis and good biocompatibility. CaO2nanoparticles have been explored for cancer treatment through three main mechanisms: (1) the release of O2, which helps alleviate tumor hypoxia and enhances oxygen-dependent therapies such as chemotherapy, photodynamic therapy, and immunotherapy; (2) the generation of H2O2, a precursor for ·OH generation, which enables cancer chemodynamic therapy; and (3) the release of Ca2+ions, which induce calcium overload and promote cell apoptosis (called ion-interference therapy). This review provides a comprehensive summary of recent examples of CaO2nanoparticle-based cancer therapeutic strategies, as well as discusses the challenges and future directions in the development of CaO2nanomedicines for cancer treatment.

Biocompatible phospholipid-based nanovesicular drug delivery system of ketoprofen: Systematic development, optimization, and preclinical evaluation.

The present work involved development of phospholipid-based permeation enhancing nanovesicles (PENVs) for topical delivery of ketoprofen. Screening of phospholipids and process parameters was performed. Central composite design was used for optimization of factors, that is, amount (%, w/w) of phospholipid and ethanol at three levels. The optimized nanovesicles (NVs) were loaded with different terpenes and then incorporated into a gel base. Optimized NVs exhibited 69% entrapment efficiency, 51% transmittance, 328 nm mean vesicle size, and polydispersity index of 0.25. In vitro release kinetics evaluation indicated best fitting as per Korsemeyer-Peppa's model and drug release via Fickian-diffusion mechanism. The optimized NVs loaded with mint terpene showed minimal degree of deformability and maximal elasticity as compared with the conventional NVs and liposomes. Rheology and texture analysis indicated pseudoplastic flow and smooth texture of the vesicle gel formulation. Ex vivo permeation studies across Wistar rat skin indicated low penetration (0.43-fold decrease) and high skin retention (4.26-fold increase) of ketoprofen from the optimized PENVs gel vis-à-vis the conventional gel. Skin irritancy study indicated lower scores for PENVs gel construing its biocompatible nature. Stability studies confirmed cold storage is best suitable for vesicle gel, and optimized PENVs were found to be suitable for topical delivery of ketoprofen.

Nano-engineering nanomedicines with customized functions for tumor treatment applications.

Nano-engineering with unique "custom function" capability has shown great potential in solving technical difficulties of nanomaterials in tumor treatment. Through tuning the size and surface properties controllablly, nanoparticles can be endoewd with tailored structure, and then the characteristic functions to improve the therapeutic effect of nanomedicines. Based on nano-engineering, many have been carried out to advance nano-engineering nanomedicine. In this review, the main research related to cancer therapy attached to the development of nanoengineering nanomedicines has been presented as follows. Firstly, therapeutic agents that target to tumor area can exert the therapeutic effect effectively. Secondly, drug resistance of tumor cells can be overcome to enhance the efficacy. Thirdly, remodeling the immunosuppressive microenvironment makes the therapeutic agents work with the autoimmune system to eliminate the primary tumor and then prevent tumor recurrence and metastasis. Finally, the development prospects of nano-engineering nanomedicine are also outlined.

Theranostic applications of selenium nanomedicines against lung cancer.

The incidence and mortality rates of lung cancer are among the highest in the world. Traditional treatment methods include surgery, chemotherapy, and radiotherapy. Although rapid progress has been achieved in the past decade, treatment limitations remain. It is therefore imperative to identify safer and more effective therapeutic methods, and research is currently being conducted to identify more efficient and less harmful drugs. In recent years, the discovery of antitumor drugs based on the essential trace element selenium (Se) has provided good prospects for lung cancer treatments. In particular, compared to inorganic Se (Inorg-Se) and organic Se (Org-Se), Se nanomedicine (Se nanoparticles; SeNPs) shows much higher bioavailability and antioxidant activity and lower toxicity. SeNPs can also be used as a drug delivery carrier to better regulate protein and DNA biosynthesis and protein kinase C activity, thus playing a role in inhibiting cancer cell proliferation. SeNPs can also effectively activate antigen-presenting cells to stimulate cell immunity, exert regulatory effects on innate and regulatory immunity, and enhance lung cancer immunotherapy. This review summarizes the application of Se-based species and materials in lung cancer diagnosis, including fluorescence, MR, CT, photoacoustic imaging and other diagnostic methods, as well as treatments, including direct killing, radiosensitization, chemotherapeutic sensitization, photothermodynamics, and enhanced immunotherapy. In addition, the application prospects and challenges of Se-based drugs in lung cancer are examined, as well as their forecasted future clinical applications and sustainable development.

Functionalization of curcumin nanomedicines: a recent promising adaptation to maximize pharmacokinetic profile, specific cell internalization and anticancer efficacy against breast cancer.

Owing to its diverse heterogeneity, aggressive nature, enormous metastatic potential, and high remission rate, the breast cancer (BC) is among the most prevalent types of cancer associated with high mortality. Curcumin (Cur) is a potent phytoconstituent that has gained remarkable recognition due to exceptional biomedical viability against a wide range of ailments including the BC. Despite exhibiting a strong anticancer potential, the clinical translation of Cur is restricted due to intrinsic physicochemical properties such as low aqueous solubility, chemical instability, low bioavailability, and short plasma half-life. To overcome these shortcomings, nanotechnology-aided developments have been extensively deployed. The implication of nanotechnology has pointedly improved the physicochemical properties, pharmacokinetic profile, cell internalization, and anticancer efficacy of Cur; however, majority of Cur-nanomedicines are still facing grandeur challenges. The advent of various functionalization strategies such as PEGylation, surface decoration with different moieties, stimuli-responsiveness (i.e., pH, light, temperature, heat, etc.), tethering of specific targeting ligand(s) based on the biochemical targets (e.g., folic acid receptors, transferrin receptors, CD44, etc.), and multifunctionalization (multiple functionalities) has revolutionized the fate of Cur-nanomedicines. This study ponders the biomedical significance of various Cur-nanomedicines and adaptable functionalizations for amplifying the physicochemical properties, cytotoxicity via induction of apoptosis, cell internalization, bioavailability, passive and active targeting to the tumor microenvironment (TME), and anticancer efficacy of the Cur while reversing the multidrug resistance (MDR) and reoccurrence in BC. Nevertheless, the therapeutic outcomes of Cur-nanomedicines against the BC have been remarkably improved after adaptation of various functionalizations; however, this evolving strategy still demands extensive research for scalable clinical translation.

Biomimetic nanovesicle co-delivery system impairs energy metabolism for cancer treatment.

Metabolic reprogramming in cancer cells plays a crucial role in cancer development, metastasis and invasion. Cancer cells have a unique metabolism profile that could switch between glycolysis and oxidative phosphorylation (OXPHOS) in order to satisfy a higher proliferative rate and enable survival in tumor microenvironment. Although dietary-based cancer starvation therapy has shown some positive outcomes for cancer treatment, it is difficult for patients to persist for a long time due to the adverse effects. Here in this study, we developed a specific M1 macrophage-derived membrane-based drug delivery system for breast cancer treatment. Both metformin and 3-Bromopyruvate were loaded into the engineered cell membrane-based biomimetic carriers (Met-3BP-Lip@M1) for the shutdown of energy metabolism in cancer cells via simultaneous inhibition of both glycolysis and oxygen consumption. The in vitro studies showed that Met-3BP-Lip@M1 had excellent cancer cell uptake and enhanced cancer cell apoptosis via cell cycle arrest. Our results also demonstrated that this novel biomimetic nanomedicine-based cancer starvation therapy synergistically improved the therapeutic efficiency against breast cancer cells by blocking energy metabolic pathways, which resulted in a significant reduction of cancer cell proliferation, 3D tumor spheroid growth as well as in vivo tumor growth.

Glucocorticoid nanoformulations relieve chronic pelvic pain syndrome and may alleviate depression in mice.

BACKGROUND: Chronic pelvic pain syndrome (CPPS) is a typical symptom of chronic prostatitis (CP) in males that may cause abnormal urination, sexual dysfunction, or depression and significantly affect the quality of life of the patient. Currently, there is no effective treatment for CPPS due to its recurrence and intractability. For synergistic CPPS therapy, we developed pH/reactive oxygen species (ROS) dual-responsive dexamethasone (Dex) nanoformulations using a ROS-responsive moiety and phytochemical modified α-cyclodextrin (α-CD) as the carrier. RESULTS: Dex release from the nanoformulations can be controlled in acidic and/or ROS-rich microenvironments. The fabricated Dex nanoformulations can also be efficiently internalized by lipopolysaccharide (LPS)-stimulated macrophages, prostatic epithelial cells, and stromal cells. Moreover, the levels of proinflammatory factors (e.g., TNF-α, IL-1ß, and IL-17 A) in these cells were significantly decreased by Dex nanoformulations treatment through the release of Dex, phytochemical and elimination of ROS. In vivo experiments demonstrated notable accumulation of the Dex nanoformulations in prostate tissue to alleviate the symptoms of CPPS through the downregulation of proinflammatory factors. Interestingly, depression in mice may be relieved due to alleviation of their pelvic pain. CONCLUSION: We fabricated Dex nanoformulations for the effective management of CPPS and alleviation of depression in mice.

Nano biomaterials based strategies for enhanced brain targeting in the treatment of neurodegenerative diseases: an up-to-date perspective.

Neurons and their connecting axons gradually degenerate in neurodegenerative diseases (NDs), leading to dysfunctionality of the neuronal cells and eventually their death. Drug delivery for the treatment of effected nervous system is notoriously complicated because of the presence of natural barriers, i.e., the blood-brain barrier and the blood cerebrospinal fluid barrier. Palliative care is currently the standard care for many diseases. Therefore, treatment programs that target the disease's origin rather than its symptoms are recommended. Nanotechnology-based drug delivery platforms offer an innovative way to circumvent these obstacles and deliver medications directly to the central nervous system, thereby enabling treatment of several common neurological problems, i.e., Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. Interestingly, the combination of nanomedicine and gene therapy enables targeting of selective mutant genes responsible for the progression of NDs, which may provide a much-needed boost in the struggle against these diseases. Herein, we discussed various central nervous system delivery obstacles, followed by a detailed insight into the recently developed techniques to restore neurological function via the differentiation of neural stem cells. Moreover, a comprehensive background on the role of nanomedicine in controlling neurogenesis via differentiation of neural stem cells is explained. Additionally, numerous phytoconstituents with their neuroprotective properties and molecular targets in the identification and management of NDs are also deliberated. Furthermore, a detailed insight of the ongoing clinical trials and currently marketed products for the treatment of NDs is provided in this manuscript.

Targeting Breast Cancer Signaling via Phytomedicine and Nanomedicine.

BACKGROUND: The development of breast cancer (BC) and how it responds to treatment have both been linked to the involvement of inflammation. Chronic inflammation is critical in carcinogenesis, leading to elevated DNA damage, impaired DNA repair machinery, cell growth, apoptosis, angiogenesis, and invasion. Studies have found several targets that selectively modulate inflammation in cancer, limit BC's growth, and boost treatment effectiveness. Drug resistance and the absence of efficient therapeutics for metastatic and triple-negative BC contribute to the poor outlook of BC patients. SUMMARY: To treat BC, small-molecule inhibitors, phytomedicines, and nanoparticles are conjugated to attenuate BC signaling pathways. Due to their numerous target mechanisms and strong safety records, phytomedicines and nanomedicines have received much attention in studies examining their prospects as anti-BC agents by such unfulfilled demands. KEY MESSAGES: The processes involved in the affiliation across the progression of tumors and the spread of inflammation are highlighted in this review. Furthermore, we included many drugs now undergoing clinical trials that target cancer-mediated inflammatory pathways, cutting-edge nanotechnology-derived delivery systems, and a variety of phytomedicines that presently address BC.

The Regulatory Landscape of New Health Technologies and Nanotechnologies: The Role of Complexity of Nanosystems.

Herein we present the modern issue of new health technologies that emerge in Medicine and Therapeutics, with regard to their development, regulatory framework, approval, and post-approval monitoring. The European law and legislation distinguish the various subcategories of health technologies in medicinal products, medical devices, biotechnological products, advanced therapy medicinal products, and nanomedicinal products. Each of these categories presents its own distinctive characteristics, based on principles that regard the development technology and intended therapeutic use, and, as a result, is defined by a unique regulatory framework inside the European legislation environment. New health technologies are a key of twenty-first-century knowledge, science, and economy and a part of society growth and economic development, while at the same time they present significant challenges, mainly through matters that regard their safety, efficacy, and value for the public. In this environment, the concept of complexity of living and artificial systems arises, as part of their nature, but also as a perspective that will give answers regarding their dynamic behavior, evolution, and overall quality.