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Carriers are equally important as drugs. They can substantially improve bioavailability of cargos and safeguard healthy cells from toxic effects of certain therapeutics. Recently, polymeric nanocarriers (PNCs) have achieved significant success in delivering drugs not only to cells but also to subcellular organelles. Variety of natural sources, availability of different synthetic routes, versatile molecular architectures, exploitable physicochemical properties, biocompatibility, and biodegradability have presented polymers as one of the most desired materials for nanocarrier design. Recent innovative concepts and advances in PNC‐associated nanotechnology are providing unprecedented opportunities to engineer nanocarriers and their functions. The efficiency of therapeutic loading has got considerably increased. Structural design‐based varieties of PNCs are widely employed for the delivery of small therapeutic molecules to genes, and proteins. PNCs have gained ever‐increasing attention and certainly paves the way to develop advanced nanomedicines. This article presents a comprehensive investigation of structural design‐based varieties of PNCs and the influences of their physicochemical properties on drug delivery profiles with perspectives highlighting the inevitability of incorporating both the multi‐stimuli‐responsive and multi‐drug delivery properties in a single carrier to design intelligent PNCs as new and emerging research directions in this rapidly developing area. Ease of designing polymeric nanocarriers (PNCs) in various structures is one of the prominent reasons for their widespread use in biomedical applications. This review focuses on exploring structure‐based varieties of PNCs and influences of their physicochemical properties on their drug delivery profiles. It also highlights the use of multi‐stimuli responsive multi‐drug delivery PNCs as new and emerging research direction.

Multidrug resistance (MDR) is regarded as one of the bottlenecks of successful clinical treatment for numerous chemotherapeutic agents. Multiple key regulators are alleged to be responsible for MDR and making the treatment regimens ineffective. In this review, we discuss MDR in relation to P-glycoprotein (P-gp) and its down-regulation by natural bioactive molecules. P-gp, a unique ATP-dependent membrane transport protein, is one of those key regulators which are present in the lining of the colon, endothelial cells of the blood brain barrier (BBB), bile duct, adrenal gland, kidney tubules, small intestine, pancreatic ducts and in many other tissues like heart, lungs, spleen, skeletal muscles, etc. Due to its diverse tissue distribution, P-gp is a novel protective barrier to stop the intake of xenobiotics into the human body. Over-expression of P-gp leads to decreased intracellular accretion of many chemotherapeutic agents thus assisting in the development of MDR. Eventually, the effectiveness of these drugs is decreased. P-gp inhibitors act by altering intracellular ATP levels which are the source of energy and/or by affecting membrane contours to increase permeability. However, the use of synthetic inhibitors is known to cause serious toxicities. For this reason, the search for more potent and less toxic P-gp inhibitors of natural origin is underway. The present review aims to recapitulate the research findings on bioactive constituents of natural origin with P-gp inhibition characteristics. Natural bioactive constituents with P-gp modulating effects offer great potential for semi-synthetic modification to produce new scaffolds which could serve as valuable investigative tools to recognize the function of complex ABC transporters apart from evading the systemic toxicities shown by synthetic counterparts. Despite the many published scientific findings encompassing P-gp inhibitors, however, this article stand alones because it provides a vivid picture to the readers pertaining to Pgp inhibitors obtained from natural sources coupled with their mode of action and structures. It provides first-hand information to the scientists working in the field of drug discovery to further synthesise and discover new P-gp inhibitors with less toxicity and more efficacies.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a global threat. We therefore analysed the bacterial characteristics of CRKP infections and the clinical outcomes of patients with CRKP infections across different countries. In this prospective, multicentre, cohort study (CRACKLE-2), hospitalised patients with cultures positive for CRKP were recruited from 71 hospitals in Argentina, Australia, Chile, China, Colombia, Lebanon, Singapore, and the USA. The first culture positive for CRKP was included for each unique patient. Clinical data on post-hospitalisation death and readmission were collected from health records, and whole genome sequencing was done on all isolates. The primary outcome was a desirability of outcome ranking at 30 days after the index culture, and, along with bacterial characteristics and 30-day all-cause mortality (a key secondary outcome), was compared between patients from China, South America, and the USA. The desirability of outcome ranking was adjusted for location before admission, Charlson comorbidity index, age at culture, Pitt bacteremia score, and anatomical culture source through inverse probability weighting; mortality was adjusted for the same confounders, plus region where relevant, through multivariable logistic regression. This study is registered at ClinicalTrials.gov, NCT03646227, and is complete. Between June 13, 2017, and Nov 30, 2018, 991 patients were enrolled, of whom 502 (51%) met the criteria for CRKP infection and 489 (49%) had positive cultures that were considered colonisation. We observed little intra-country genetic variation in CRKP. Infected patients from the USA were more acutely ill than were patients from China or South America (median Pitt bacteremia score 3 [IQR 2–6] vs 2 [0–4] vs 2 [0–4]) and had more comorbidities (median Charlson comorbidity index 3 [IQR 2–5] vs 1 [0–3] vs 1 [0–2]). Adjusted desirability of outcome ranking outcomes were similar in infected patients from China (n=246), South America (n=109), and the USA (n=130); the estimates were 53% (95% CI 42–65) for China versus South America, 50% (41–61) for the USA versus China, and 53% (41–66) for the USA versus South America. In patients with CRKP infections, unadjusted 30-day mortality was lower in China (12%, 95% CI 8–16; 29 of 246) than in the USA (23%, 16–30; 30 of 130) and South America (28%, 20–37; 31 of 109). Adjusted 30-day all-cause mortality was higher in South America than in China (adjusted odds ratio [aOR] 4·82, 95% CI 2·22–10·50) and the USA (aOR 3·34, 1·50–7·47), with the mortality difference between the USA and China no longer being significant (aOR 1·44, 0·70–2·96). Global CRKP epidemics have important regional differences in patients’ baseline characteristics and clinical outcomes, and in bacterial characteristics. Research findings from one region might not be generalisable to other regions. The National Institutes of Health.

Silver nanoparticles (AgNPs) are the most investigated antibacterial agents against multidrug resistant (MDR) pathogens. They can lead to cellular death by means of different mechanisms, damaging several cell compartments, from the external membrane, to enzymes, DNA and proteins; this simultaneous attack amplifies the toxic effect on bacteria with respect to traditional antibiotics. The effectiveness of AgNPs against MDR bacteria is strongly correlated with their chemical and morphological properties, which influence the pathways involved in cellular damage. In this review, AgNPs’ size, shape and modification by functional groups or other materials are reported, both to investigate the different synthetic pathways correlated with nanoparticles’ modifications and to evaluate the related effect on their antibacterial activity. Indeed, understanding the synthetic conditions for obtaining performing antibacterial AgNPs could help to tailor new and improved silver-based agents to combat multidrug resistance.

Cancer treatment faces many hurdles and resistance is one among them. Anti-cancer treatment strategies are evolving due to innate and acquired resistance capacity, governed by genetic, epigenetic, proteomic, metabolic, or microenvironmental cues that ultimately enable selected cancer cells to survive and progress under unfavorable conditions. Although the mechanism of drug resistance is being widely studied to generate new target-based drugs with better potency than existing ones. However, due to the broader flexibility in acquired drug resistance, advanced therapeutic options with better efficacy need to be explored. Combination therapy is an alternative with a better success rate though the risk of amplified side effects is commonplace. Moreover, recent groundbreaking precision immune therapy is one of the ways to overcome drug resistance and has revolutionized anticancer therapy to a greater extent with the only limitation of being individual-specific and needs further attention. This review will focus on the challenges and strategies opted by cancer cells to withstand the current therapies at the molecular level and also highlights the emerging therapeutic options -like immunological, and stem cell-based options that may prove to have better potential to challenge the existing problem of therapy resistance. 3-XVUB_ebN3hwzsWHiRmg5 Video Abstract

Background The use of inhaled antibiotics for treating pneumonia in invasively ventilated patients offers a direct approach, allowing for high local concentrations of the drug in the lower respiratory tract while simultaneously reducing systemic toxicity. However, the real efficacy and safety of nebulized antibiotics remain unclear. The aim of the present is to assess among critically adult patients with pneumonia and invasive ventilation, whether receiving adjuvant inhaled antibiotics improves the rate of microbiological eradication. Methods A comprehensive literature search of randomized clinical trials (RCTs) was conducted (from inception until September 20, 2024, PROSPERO-CRD592906) across Medline, Embase, and Scopus. Randomized controlled trials, enrolling intensive care units (ICU) patients with pneumonia and comparing nebulized antimicrobial therapy (inhaled group) with intravenous antimicrobial treatment or intravenous antimicrobial therapy plus inhaled placebo (control group), were included. The primary outcome was the rate of microbiological eradication after treatment. Secondary outcomes were the rate of clinical recovery, the incidence of drug-related adverse events, ICU and hospital mortality. A qualitative analysis was conducted according to the GRADE framework. Data were pooled using an odds-ratio analysis. The heterogeneity and reliability of our results were evaluated using the I 2 -statistic and trial sequential analysis (TSA), respectively. Results A total of 11 RCTs (1472 patients) met the inclusion criteria. Compared to controls, the use of adjuvant inhaled antibiotics determined a greater rate of microbiological eradication (OR 2.63, 95% CI 1.36–5.09; low certainty of evidence). The TSA confirmed the reliability of our primary outcome. Moreover, nebulized antibiotics increased the risk of bronchospasm (OR 3.15, 95% CI 1.33–7.47; high evidence), while nephrotoxicity, clinical recovery, ICU and hospital survival (either in the case of pneumonia caused by MDR bacteria or not) were not different between groups. Conclusions In conclusion, compared to the sole intravenous therapy, the use of adjuvant inhaled antibiotics for treatment of pneumonia in invasively ventilated critically ill patients was associated with a greater incidence of microbiological eradication (low GRADE and high risk of publication bias), but not with clinical recovery and survival.

Bacteriophages (BPs) are viruses that can infect and kill bacteria without any negative effect on human or animal cells. For this reason, it is supposed that they can be used, alone or in combination with antibiotics, to treat bacterial infections. In this narrative review, the advantages and limitations of BPs for use in humans will be discussed. PubMed was used to search for all of the studies published from January 2008 to December 2018 using the key words: \"BPs\" or \"phages\" and \"bacterial infection\" or \"antibiotic\" or \"infectious diseases.\" More than 100 articles were found, but only those published in English or providing evidence-based data were included in the evaluation. Literature review showed that the rapid rise of multi-drug-resistant bacteria worldwide coupled with a decline in the development and production of novel antibacterial agents have led scientists to consider BPs for treatment of bacterial infection. Use of BPs to overcome the problem of increasing bacterial resistance to antibiotics is attractive, and some research data seem to indicate that it might be a rational measure. However, present knowledge seems insufficient to allow the use of BPs for this purpose. To date, the problem of how to prepare the formulations for clinical use and how to avoid or limit the risk of emergence of bacterial resistance through the transmission of genetic material are not completely solved problems. Further studies specifically devoted to solve these problems are needed before BPs can be used in humans.

Leishmaniasis is one of the most important tropical neglected diseases according to the World Health Organization. Even after more than a century, we still have few drugs for the disease therapy and their great toxicity and side effects put in check the treatment control program around the world. Moreover, the emergence of strains resistant to conventional drugs, co-infections such as HIV/Leishmania spp., the small therapeutic arsenal (pentavalent antimonials, amphotericin B and formulations, and miltefosine), and the low investment for the discovery/development of new drugs force researchers and world health agencies to seek new strategies to combat and control this important neglected disease. In this context, the aim of this review is to summarize new advances and new strategies used on leishmaniasis therapy addressing alternative and innovative treatment paths such as physical and local/topical therapies, combination or multi-drug uses, immunomodulation, drug repurposing, and the nanotechnology-based drug delivery systems.Key points• The treatment of leishmaniasis is a challenge for global health agencies.• Toxicity, side effects, reduced therapeutic arsenal, and drug resistance are the main problems.• New strategies and recent advances on leishmaniasis treatment are urgent.• Immunomodulators, nanotechnology, and drug repurposing are the future of leishmaniasis treatment.

Anticancer drugs resistance is a complex process that arises from altering in the drug targets. Advances in the DNA microarray, proteomics technology and the development of targeted therapies provide the new strategies to overcome the drug resistance. Although a design of the new chemotherapy agents is growing quickly, effective chemotherapy agent has not been discovered against the advanced stage of cancer (such as invasion and metastasis). The cancer cell resistance against the anticancer agents can be due to many factors such as the individual’s genetic differences, especially in tumoral somatic cells. Also, the cancer drug resistance is acquired, the drug resistance can be occurred by different mechanisms, including multi-drug resistance, cell death inhibiting (apoptosis suppression), altering in the drug metabolism, epigenetic and drug targets, enhancing DNA repair and gene amplification. In this review, we outlined the mechanisms of cancer drug resistance and in following, the treatment failures by common chemotherapy agents in the different type of cancers.