Pembrolizumab-Induced Ketoacidosis: A Case Report.

Immune checkpoint inhibitors (ICIs), such as pembrolizumab, have transformed immuno-oncology by demonstrating efficacy against various cancers, including small-cell lung carcinoma and HER2-positive gastric cancer. Despite their benefits, ICIs can provoke immune-related adverse events, with endocrinopathies being rare but carrying significant complications. We report a case of pembrolizumab-induced diabetic ketoacidosis (DKA) in an 87-year-old woman with advanced gastric carcinoma and no prior diabetes history. The patient presented with acute hyperglycemia and metabolic acidosis and was found to have low C-peptide levels without other autoimmune markers typically associated with type 1 diabetes. This case highlights the need for awareness of pembrolizumab as a potential trigger for DKA, especially in patients without a prior diabetes diagnosis. While the management of DKA remains the same, identifying the precipitating factor allows for a comprehensive diagnostic workup and effective long-term management, maintaining the patient's quality of life. This case highlights the complexities of managing DKA in ICI therapy and illustrates the importance of distinguishing between classical DKA presentations and those related to ICIs.

LC-SRM combined with machine learning enables fast identification and quantification of bacterial pathogens in urinary tract infections.

Urinary tract infections (UTIs) are a worldwide health problem. Fast and accurate detection of bacterial infection is essential to provide appropriate antibiotherapy to patients and to avoid the emergence of drug-resistant pathogens. While the gold standard requires 24h to 48h of bacteria culture prior MALDI-TOF species identification, we propose a culture-free workflow, enabling a bacterial identification and quantification in less than 4 hours using 1mL of urine. After a rapid and automatable sample preparation, a signature of 82 bacterial peptides, defined by machine learning, was monitored in LC-MS, to distinguish the 15 species causing 84% of the UTIs. The combination of the sensitivity of the SRM mode on a triple quadrupole TSQ Altis instrument and the robustness of capillary flow enabled us to analyze up to 75 samples per day, with 99.2% accuracy on bacterial inoculations of healthy urines. We have also shown our method can be used to quantify the spread of the infection, from 8x104 to 3x107 CFU/mL. Finally, the workflow was validated on 45 inoculated urines and on 84 UTI-positive urine from patients, with respectively 93.3% and 87.1% of agreement with the culture-MALDI procedure at a level above 1x105 CFU/mL corresponding to an infection requiring antibiotherapy.

Chemical engineering of zein with polyethylene glycol and Angiopep-2 to manufacture a brain-targeted docetaxel nanomedicine for glioblastoma treatment.

Glioblastoma (GBM) is the deadliest adult brain cancer. The current standard-of-care chemotherapy using orally administered temozolomide (TMZ) presents poor improvement in patient survival, emphasizing the compelling need for new therapies. A possible chemotherapeutic alternative is docetaxel (DTX), which possesses higher tumoricidal potency against GBM cells. However, its limited blood-brain barrier (BBB) permeability poses a constraint on its application. Nonetheless, nanomedicine offers promising avenues for overcoming this challenge. Angiopep-2 (ANG2) is a peptide that targets the BBB-overexpressed low-density lipoprotein receptor (LDLR). In this work, we managed, for the first time, to employ a pioneering approach of covalently linking zein protein with polyethylene glycol (PEG) and ANG2 prior to its formulation into nanoparticles (ZNPs) with enhanced stability and LDLR-mediated brain targetability, respectively. Carbodiimide and click chemistry approaches were optimized, resulting in functional modification of zein with around 25% PEG, followed by functional modification of PEG with nearly 100% ANG2. DTX-loaded ZNPs presented 100 nm average size, indicating high suitability for BBB crossing through receptor-mediated transcytosis. ZNPs maintained the cytotoxic effect of the loaded DTX against GBM cells, while demonstrating a safe matrix against BBB cells. Importantly, these brain-targeted ZNPs showcased up to fourfold enhancement in blood-to-brain permeability in a BBB in vitro model, highlighting the potential of this novel approach of BBB targeting in significantly improving therapeutic outcomes for GBM patients. The versatility of the system and the possibility of significantly increasing drug concentration in the brain open the door to its future application in a wide range of other brain-related diseases.

Orally Delivered Stimulus-Sensitive Nanomedicine to Harness Teduglutide Efficacy in Inflammatory Bowel Disease.

Inflammatory Bowel Disease (IBD) is a chronic inflammatory condition affecting the gastrointestinal tract (GIT). Glucagon-like peptide-2 (GLP-2) analogs possess high potential in the treatment of IBD by enhancing intestinal repair and attenuating inflammation. Due to the enzymatic degradation and poor intestinal absorption, GLP-2 analogs are administered parenterally, which leads to poor patient compliance. This work aims to develop IBD-targeted nanoparticles (NPs) for the oral delivery of the GLP-2 analog, Teduglutide (TED). Leveraging the overproduction of Reactive Oxygen Species (ROS) in the IBD environment, ROS-sensitive NPs are developed to target the intestinal epithelium, bypassing the mucus barrier. PEGylation of NPs facilitates mucus transposition, but subsequent PEG removal is crucial for cellular internalization. This de-PEGylation is possible by including a ROS-sensitive thioketal linker within the system. ROS-sensitive NPs are established, with the ability to fully de-PEGylate via ROS-mediated cleavage. Encapsulation of TED into NPs resulted in the absence of absorption in 3D in vitro models, potentially promoting a localized action, and avoiding adverse effects due to systemic absorption. Upon oral administration to colitis-induced mice, ROS-sensitive NPs are located in the colon, displaying healing capacity and reducing inflammation. Cleavable PEGylated NPs demonstrate effective potential in managing IBD symptoms and modulating the disease's progression.

A Trapping-Micro-LC-FAIMS/dCV-MS Strategy for Ultrasensitive and Robust Targeted Quantification of Protein Drugs and Biomarkers.

The sensitivity of LC-MS in quantifying target proteins in plasma/tissues is significantly hindered by coeluted matrix interferences. While antibody-based immuno-enrichment effectively reduces interferences, developing and optimizing antibodies are often time-consuming and costly. Here, by leveraging the orthogonal separation capability of Field Asymmetric Ion Mobility Spectrometry (FAIMS), we developed a FAIMS/differential-compensation-voltage (FAIMS/dCV) method for antibody-free, robust, and ultrasensitive quantification of target proteins directly from plasma/tissue digests. By comparing the intensity-CV profiles of the target vs coeluted endogenous interferences, the FAIMS/dCV approach identifies the optimal CV for quantification of each target protein, thus maximizing the signal-to-noise ratio (S/N). Compared to quantification without FAIMS, this technique dramatically reduces endogenous interferences, showing a median improvement of the S/N by 14.8-fold for the quantification of 17 representative protein drugs and biomarkers in plasma or tissues and a 5.2-fold median increase in S/N over conventional FAIMS approach, which uses the peak CV of each target. We also discovered that the established CV parameters remain consistent over months and are matrix-independent, affirming the robustness of the developed FAIMS/dCV method and the transferability of the method across matrices. The developed method was successfully demonstrated in three applications: the quantification of monoclonal antibodies with subng/mL LOQ in plasma, an investigation of the time courses of evolocumab and its target PCSK9 in a preclinical setting, and a clinical investigation of low abundance obesity-related biomarkers. This innovative and easy-to-use method has extensive potential in clinical and pharmaceutical research, particularly where sensitive and high-throughput quantification of protein drugs and biomarkers is required.

Metabarcoding expands knowledge on diversity and ecology of rare actinobacteria in the Brazilian Cerrado.

Rare and unknown actinobacteria from unexplored environments have the potential to produce new bioactive molecules. This study aimed to use 16 s rRNA metabarcoding to determine the composition of the actinobacterial community, particularly focusing on rare and undescribed species, in a nature reserve within the Brazilian Cerrado called Sete Cidades National Park. Since this is an inaccessible area without due legal authorization, it is understudied, and, therefore, its diversity and biotechnological potential are not yet fully understood, and it may harbor species with groundbreaking genetic potential. In total, 543 operational taxonomic units (OTUs) across 14 phyla were detected, with Actinobacteria (41.2%), Proteobacteria (26.5%), and Acidobacteria (14.3%) being the most abundant. Within Actinobacteria, 107 OTUs were found, primarily from the families Mycobacteriaceae, Pseudonocardiaceae, and Streptomycetaceae. Mycobacterium and Streptomyces were the predominant genera across all samples. Seventeen rare OTUs with relative abundance < 0.1% were identified, with 82.3% found in only one sample yet 25.5% detected in all units. Notable rare and transient genera included Salinibacterium, Nocardia, Actinomycetospora_01, Saccharopolyspora, Sporichthya, and Nonomuraea. The high diversity and distribution of Actinobacteria OTUs indicate the area's potential for discovering new rare species. Intensified prospection on underexplored environments and characterization of their actinobacterial diversity could lead to the discovery of new species capable of generating innovative natural products.

Epidemiology of Musculoskeletal Injuries in Golf Athletes: A Championship in Portugal.

Although golf is a low-impact sport without physical contact, its movements are carried out over a large range of motion, and their repetition can predispose athletes to the development of injuries. This study aimed to investigate the epidemiology of musculoskeletal injuries in golf athletes who participated in championships in southern Portugal, determining the types, locations and mechanisms of injury and their associated risk factors. The sample consisted of 140 athletes aged between 18 and 72 years, 133 (95%) being male. The measuring instrument was a questionnaire about sociodemographics, modality and injuries' characteristics. Throughout golf practice, 70 (50%) athletes reported injuries, totaling 133 injuries. In the 12-month period, 43 (30.7%) athletes suffered injuries, totaling 65 injuries. The injury proportion was of 0.31, and the injury rate was of 0.33 injuries per 1000 h of golf training. The most common injury type was muscle sprain or rupture (19; 30.9%), located in the lumbar spine (17; 27%), in which the repetitive movements were the main injury mechanism (42; 66.7%). The athletes who trained 4 times or more per week were 3.5 more likely (CI: 0.97-12.36; p = 0.056) to develop an injury while playing golf. Moderate injury presence was observed, with the high training frequency being an associated risk factor.

Genomic and epidemiological insight of an outbreak of carbapenemase-producing Enterobacterales in a Portuguese hospital with the emergence of the new KPC-124.

BACKGROUND: Carbapenemase-producing Enterobacterales (CPE) is an increasing problem in healthcare settings. This study aimed to identify the source of a CPE outbreak that occurred in 2022, in a tertiary hospital in the North of Portugal, to identify exposed patients, and to assess the risk of becoming CPE-positive following hospital admission. METHODS: A multi-disciplinary investigation was conducted including descriptive, analytical, and molecular epidemiology, environmental screening, and assessment of infection control measures. Clinical and environmental isolates were analyzed using whole-genome sequencing and phylogenetic analysis. Additionally, a prospective observational cohort study was conducted to further investigate the risk factors associated with the emergence of new cases in cohorts of CPE-negative admitted patients. RESULTS: We observed the presence of multispecies KPC-, IMP-, and/or NDM-producing isolates. Genetically indistinguishable clinical and environmental isolates were found on the same room/ward. The ST45 KPC-3-producing Klebsiella pneumoniae clone was the responsible for the outbreak. During patients' treatment, we detected the emergence of resistance to ceftazidime-avibactam, associated with mutations in the blaKPC-3 gene (blaKPC-46, blaKPC-66 and blaKPC-124, the last variant never previously reported), suggesting a vertical evolutionary trajectory. Patients aged ≥ 75 years, hygiene/feeding-care dependent, and/or subjected to secretion aspiration were risk factors for CPE colonization after hospital admission. Additionally, cases with previous admission to the emergency department suggest that CPE dissemination may occur not only during hospitalization but also in the emergency department. CONCLUSION: Overall, the study highlights that selection pressure with antibiotics, like ceftazidime-avibactam, is a contributing factor to the emergence of new ß-lactamase variants and antibiotic resistance. It also shows that the hospital environment can be a significant source of CPE transmission, and that routine use of infection control measures and real-time molecular epidemiology investigations are essential to ensure the long-term termination of CPE outbreaks and prevent future resurgences.

Beta-Carotene Supplementation for Sows: Reproductive Parameters and Productive Performance of Piglets.

The rapid fetal development and the increased demand for milk result in a catabolic state and oxidative stress in hyperprolific sows. Despite animal defense mechanisms, the dietary supplementation of antioxidants is being evaluated to reduce the impacts of excess free radicals. The aim of this study was to evaluate the short- and long-term effects of beta-carotene supplementation for sows on the reproductive response and performance of suckling piglets. A total of 120 sows were distributed in a 3 × 4 factorial arrangement of three supplementation levels (B0-no supplementation, B200-200 mg beta-carotene/day and B400-400 mg beta-carotene/day) and four groups of parity order (1st, 2nd, 3rd, above 4th). Beta-carotene supplementation during lactation resulted in a higher litter weight at weaning. A higher average weight of piglets and litter weight at birth were observed, as well as a greater number of piglets weaned and litter weight at weaning in sows supplemented with 400 mg of beta-carotene during gestation and lactation periods. Supplementation with 200 and 400 mg of beta-carotene resulted in a greater weight at weaning and daily weight gain in piglets. Daily supplementation with 400 mg of beta-carotene in the prepartum and lactation phases provides a greater litter weight at weaning and, when supplemented in the pre-gestation and gestation periods, results in a greater litter weight at birth and at weaning.

Longitudinal Predictors of Word Reading for Children with Williams Syndrome.

We examined the cognitive, language, and instructional predictors of early word-reading ability in a sample of children with Williams syndrome longitudinally. At Time 1, sixty-nine 6-7-year-olds (mean age = 6.53 years) completed standardized measures of phonological awareness, visual-spatial perception, vocabulary, and overall intellectual ability. Word-reading instruction type was classified as (systematic) Phonics (n = 35) or Other (n = 34). At Time 2, approximately three years later (mean age = 9.47 years), children completed a standardized assessment of single-word reading ability. Reading ability at Time 2 varied considerably, from inability to read any words to word-reading ability slightly above the level expected for age. The results of a multiple regression indicated that Time 1 word-reading instruction type, phonological awareness, and visual-spatial perception (as assessed by a matching letter-like forms measure) each explained significant unique variance in word reading at Time 2. A systematic phonics approach was associated with significantly better performance than other reading-instruction approaches. Exploratory analyses suggested that the relations between these factors were complex. Considered together, these findings strongly suggest that, in line with the Cumulative Risk and Resilience Model of reading disability, word-reading (dis)ability in Williams syndrome is probabilistic in nature, resulting from the interaction of multiple individual and environmental risk and protective factors. The results also have educational implications: Early word-reading instruction for children with Williams syndrome should combine systematic phonics and phonological awareness training while also incorporating letter discrimination instruction highlighting the visual-spatial differences between similar-appearing letters.

scFv biofunctionalized nanoparticles to effective and safe targeting of CEA-expressing colorectal cancer cells.

Colorectal cancer (CRC) is one of the deadliest cancers worldwide, with the 5 year survival rate in metastatic cases limited to 12%. The design of targeted and effective therapeutics remains a major unmet clinical need in CRC treatment. Carcinoembryonic antigen (CEA), a glycoprotein overexpressed in most colorectal tumors, may constitute a promising molecule for generating novel CEA-targeted therapeutic strategies for CRC treatment. Here, we developed a smart nanoplatform based on chemical conjugation of an anti-CEA single-chain variable fragment (scFv), MFE-23, with PLGA-PEG polymers to deliver the standard 5-Fluorouracil (5-FU) chemotherapy to CRC cells. We confirmed the specificity of the developed CEA-targeted NPs on the internalization by CEA-expressing CRC cells, with an enhance of threefold in the cell uptake. Additionally, CEA-targeted NPs loaded with 5-FU induced higher cytotoxicity in CEA-expressing cells, after 24 h and 48 h of treatment, reinforcing the specificity of the targeted NPs. Lastly, the safety of CEA-targeted NPs loaded with 5-FU was evaluated in donor-isolated macrophages, with no relevant impact on their metabolic activity nor polarization. Altogether, this proof of concept supports the CEA-mediated internalization of targeted NPs as a promising chemotherapeutic strategy for further investigation in different CEA-associated cancers and respective metastatic sites.Authors: Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Author 1 Given name: [Maria José] Last name [Silveira]. Author 7 Given name: [Maria José] Last name [Oliveira]. Also, kindly confirm the details in the metadata are correctokAffiliations: Please check and confirm that the authors and their respective affiliations have been correctly identified and amend if necessary.ok.

Multi-ligand functionalized blood-to-tumor sequential targeting strategies in the field of glioblastoma nanomedicine.

Glioblastoma (GBM) is an unmet clinical need characterized by a standard of care (SOC) 5-year survival rate of only 5%, and a treatment mostly palliative. Significant hurdles in GBM therapies include an effective penetration of therapeutics through the brain protective barrier, namely the blood-brain barrier (BBB), and a successful therapeutic delivery to brain-invading tumor cells post-BBB crossing. These hurdles, along with the poor prognosis and critical heterogeneity of the disease, have shifted attention to treatment modalities with capacity to precisely and sequentially target (i) BBB cells, inducing blood-to-brain transport, and (ii) GBM cells, leading to a higher therapeutic accumulation at the tumor site. This sequential targeting allows therapeutic molecules to reach the brain parenchyma and compromise molecular processes that support tumor cell invasion. Besides improving formulation and pharmacokinetics constraints of drugs, nanomedicines offer the possibility of being surface functionalized with multiple possibilities of targeting ligands, while delivering the desired therapeutic cargos to the biological sites of interest. Targeting ligands exploit the site-specific expression or overexpression of specific molecules on BBB and GBM cells, triggering brain plus tumor transport. Since the efficacy of single-ligand functionalized nanomedicines is limited due to the GBM anatomical site (brain) and disease complexity, this review presents an overview of multi-ligand functionalized, BBB and GBM sequentially- and dual-targeted nanomedicines reported in literature over the last 10 years. The role of the BBB in GBM progression, treatment options, and the multiple possibilities of currently available targeting ligands will be summarized. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Digging the intercellular crosstalk via extracellular vesicles: May exosomes be the drug delivery solution for target glioblastoma?

Glioblastoma (GBM) is an adult's most aggressive brain tumor. The advances in molecular pathology and cell signaling pathways have deepened researchers' understanding of intercellular communication mechanisms that can induce tumor progression, namely the release of extracellular vesicles. Exosomes are small extracellular vesicles in various biological fluids released by almost all cells, thus carrying various biomolecules specific to their parental cell. Several pieces of evidence indicate that exosomes mediate intercellular communication in the tumor microenvironment and cross the blood-brain barrier (BBB), valuable tools for diagnostic and therapeutic applications under the scope of brain diseases such as brain tumors. This review aims to resume the several biological characteristics and the interplay between glioblastoma and exosomes, describing highlight studies that demonstrate the role of exosomes in the tumor microenvironment of GBM and their potential for non-invasive diagnoses and therapeutic approaches, namely, as nanocarriers for drug or gene delivery and cancer vaccines.

Functionalized retinoic acid lipid nanocapsules promotes a two-front attack on inflammation and lack of demyelination on neurodegenerative disorders.

Demyelinating disorders, with a particular focus on multiple sclerosis (MS), have a multitude of detrimental cognitive and physical effects on the patients. Current treatment options that involve substances promoting remyelination fail in the clinics due to difficulties in reaching the central nervous system (CNS). Here, the dual encapsulation of retinoic acid (RA) into lipid nanocapsules with a nominal size of 70 nm, and a low PdI of 0.1, coupled with super paramagnetic iron oxide nanoparticles (SPIONs) was accomplished, and joined by an external functionalization process with a transferrin-receptor binding peptide. This nanosystem showed a 3-fold improved internalization by endothelial cells compared to the free drug, ability to interact with oligodendrocyte progenitor cells and microglia, and improvements in the permeability through the blood-brain barrier by 5-fold. The lipid nanocapsules also induced the differentiation of oligodendrocyte progenitor cells into more mature, myelin producing oligodendrocytes, as evaluated by high-throughput image screening, by 3-5-fold. Furthermore, the ability to tame the inflammatory response was verified in lipopolysaccharide-stimulated microglia, suppressing the production of pro-inflammatory cytokines by 50-70%. Overall, the results show that this nanosystem can act in both the inflammatory microenvironment present at the CNS of affected patients, but also stimulate the differentiation of new oligodendrocytes, paving the way for a promising platform in the therapy of MS.

Metabolomics to Study Human Aging: A Review.

In the last years, with the increase in the average life expectancy, the world's population is progressively aging, which entails social, health and economic problems. In this sense, the need to better understand the physiology of the aging process becomes an urgent need. Since the study of aging in humans is challenging, cellular and animal models are widely used as alternatives. Omics, namely metabolomics, have emerged in the study of aging, with the aim of biomarker discovering, which may help to uncomplicate this complex process. This paper aims to summarize different models used for aging studies with their advantages and limitations. Also, this review gathers the published articles referring to biomarkers of aging already discovered using metabolomics approaches, comparing the results obtained in the different studies. Finally, the most frequently used senescence biomarkers are described, along with their importance in understanding aging.

Stimuli-Responsive Multifunctional Nanomedicine for Enhanced Glioblastoma Chemotherapy Augments Multistage Blood-to-Brain Trafficking and Tumor Targeting.

Minimal therapeutic advances have been achieved over the past two decades for glioblastoma (GBM), which remains an unmet clinical need. Here, hypothesis-driven stimuli-responsive nanoparticles (NPs) for docetaxel (DTX) delivery to GBM are reported, with multifunctional features that circumvent insufficient blood-brain barrier (BBB) trafficking and lack of GBM targeting-two major hurdles for anti-GBM therapies. NPs are dual-surface tailored with a i) brain-targeted acid-responsive Angiopep-2 moiety that triggers NP structural rearrangement within BBB endosomal vesicles, and ii) L-Histidine moiety that provides NP preferential accumulation into GBM cells post-BBB crossing. In tumor invasive margin patient cells, the stimuli-responsive multifunctional NPs target GBM cells, enhance cell uptake by 12-fold, and induce three times higher cytotoxicity in 2D and 3D cell models. Moreover, the in vitro BBB permeability is increased by threefold. A biodistribution in vivo trial confirms a threefold enhancement of NP accumulation into the brain. Last, the in vivo antitumor efficacy is validated in GBM orthotopic models following intratumoral and intravenous administration. Median survival and number of long-term survivors are increased by 50%. Altogether, a preclinical proof of concept supports these stimuli-responsive multifunctional NPs as an effective anti-GBM multistage chemotherapeutic strategy, with ability to respond to multiple fronts of the GBM microenvironment.

Omic-Scale High-Throughput Quantitative LC-MS/MS Approach for Circulatory Lipid Phenotyping in Clinical Research.

Lipid analysis at the molecular species level represents a valuable opportunity for clinical applications due to the essential roles that lipids play in metabolic health. However, a comprehensive and high-throughput lipid profiling remains challenging given the lipid structural complexity and exceptional diversity. Herein, we present an 'omic-scale targeted LC-MS/MS approach for the straightforward and high-throughput quantification of a broad panel of complex lipid species across 26 lipid (sub)classes. The workflow involves an automated single-step extraction with 2-propanol, followed by lipid analysis using hydrophilic interaction liquid chromatography in a dual-column setup coupled to tandem mass spectrometry with data acquisition in the timed-selective reaction monitoring mode (12 min total run time). The analysis pipeline consists of an initial screen of 1903 lipid species, followed by high-throughput quantification of robustly detected species. Lipid quantification is achieved by a single-point calibration with 75 isotopically labeled standards representative of different lipid classes, covering lipid species with diverse acyl/alkyl chain lengths and unsaturation degrees. When applied to human plasma, 795 lipid species were measured with median intra- and inter-day precisions of 8.5 and 10.9%, respectively, evaluated within a single and across multiple batches. The concentration ranges measured in NIST plasma were in accordance with the consensus intervals determined in previous ring-trials. Finally, to benchmark our workflow, we characterized NIST plasma materials with different clinical and ethnic backgrounds and analyzed a sub-set of sera (n = 81) from a clinically healthy elderly population. Our quantitative lipidomic platform allowed for a clear distinction between different NIST materials and revealed the sex-specificity of the serum lipidome, highlighting numerous statistically significant sex differences.

Multifunctional nanomedicine strategies to manage brain diseases.

Brain diseases represent a substantial social and economic burden, currently affecting one in six individuals worldwide. Brain research has been focus of great attention in order to unravel the pathogenesis and complexity of brain diseases at the cellular, molecular, and microenvironmental levels. Due to the intrinsic nature of the brain, the presence of the highly restrictive blood-brain barrier (BBB), and the pathophysiology of most diseases, therapies can hardly be considered successful purely by the administration of one drug to a patient. Apart from improving pharmacokinetic parameters, tailoring biodistribution, and reducing the number of side effects, nanomedicines are able to actively co-target the therapeutics to the brain parenchyma and brain lesions, as well as to achieve the delivery of multiple cargos with therapeutic, diagnostic, and theranostic properties. Among other multivalent effects that can be personalized according to the disease needs, this represents a promising class of novel nanosystems, termed multifunctional nanomedicines. Herein, we review the principal mechanisms of therapeutic resistance of the most prevalent brain diseases, how to overcome this therapeutic resistance through the use of multifunctional nanomedicines that tackle multiple fronts of the disease microenvironment, and the promising therapeutic responses achieved by some of the most cutting-edge multifunctional nanomedicines reported in literature.