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Breast cancer (BC) is the most common type of malignancy which covers almost one-fourth of all the cancers diagnosed in women. Conventionally, chemo-, hormonal-, immune-, surgery, and radiotherapy are the clinically available therapies for BC. However, toxicity and other related adverse effects are still the major challenges. A variety of nano platforms have been reported to overcome these limitations, among them, exosomes provide a versatile platform not only for the diagnosis but also as a delivery vehicle for drugs. Exosomes are biological nanovesicles made up of a lipidic bilayer and known for cell-to-cell communication. Exosomes have been reported to be present in almost all bodily fluids, viz., blood, milk, urine, saliva, pancreatic juice, bile, peritoneal, and cerebrospinal fluid. Such characteristics of exosomes have attracted immense interest in cancer diagnosis and therapy. They can deliver bioactive moieties such as protein, lipids, hydrophilic as well as hydrophobic drugs, various RNAs to both distant and nearby recipient cells as well as have specific biological markers. By considering the growing interest of the scientific community in this field, we comprehensively compiled the information about the biogenesis of exosomes, various isolation methods, the drug loading techniques, and their diverse applications in breast cancer diagnosis and therapy along with ongoing clinical trials which will assist future scientific endeavors in a more organized direction.

Triple-negative breast cancer (TNBC) is considered one of the un-manageable types of breast cancer, involving devoid of estrogen, progesterone, and human epidermal growth factor receptor 2 (HER 2) receptors. Due to their ability of recurrence and metastasis, the management of TNBC remains a mainstay challenge, despite the advancements in cancer therapies. Conventional chemotherapy remains the only treatment regimen against TNBC and suffers several limitations such as low bioavailability, systemic toxicity, less targetability, and multi-drug resistance. Although various targeted therapies have been introduced to manage the hardship of TNBC, they still experience certain limitations associated with the survival benefits. The current research thus aimed at developing and improving the strategies for effective therapy against TNBC. Such strategies involved the emergence of nanoparticles. Nanoparticles are designated as nanocavalries, loaded with various agents (drugs, genes, etc.) to battle the progression and metastasis of TNBC along with overcoming the limitations experienced by conventional chemotherapy and targeted therapy. This article documents the treatment regimens of TNBC along with their efficacy towards different subtypes of TNBC, and the various nanotechnologies employed to increase the therapeutic outcome of FDA-approved drug regimens.

Paclitaxel (PAC) has been approved by FDA for clinical use (Taxol®), yet dose-dependent severe toxicity due to the adjuvant Cremophor EL® in combination with ethanol is a major drawback. The drawbacks of the current therapy can be overcome by (i) finding a suitable vehicle that cannot only bypass the above adjuvant but also be used to deliver drugs orally and (ii) combining the PAC with some other chemotherapeutics to have the enhanced therapeutic efficacy. In the current work, we have used folic acid (FA) functionalized bovine milk-derived exosomes for oral delivery of PAC in combination with 5-fluorouracil (5-FU). Exosomes before and after the drug loading were found to have a particle size in the range of 80–100 nm, polydispersity index (PDI ~0.20), zeta potential (~−25 mV), entrapment efficiency (~82%), practical drug loading (~28%) and sustained drug release for 48 h. Significant decreases in IC50 were observed in the case of exosomes loaded drugs which further improved following the FA functionalization. FA functionalized coumarin-6-loaded exosomes showed remarkably higher cellular uptake in comparison with free coumarin-6. Moreover, FA-functionalized drug-loaded exosomes showed a higher apoptotic index with better control over cell migration. Collectively, data suggested the enhanced efficacy of the combination following its loading to the folic acid functionalized exosomes against breast cancer.

This study explored the combined administration of docetaxel (DOC) and erlotinib (ERL) using nanostructured lipid carriers (NLCs), with folic acid (FA) conjugation to enhance their synergistic anticancer efficacy against triple-negative breast cancer. NLCs were developed through hot melt homogenization–ultrasound dispersion, and optimized by a quality-by-design (QbD) approach using Plackett–Burman design and Box–Behnken design. Plots were generated based on maximum desirability. Spherical, nanosized dispersions (<200 nm) with zeta potential ranging from −16.4 to −14.15 mV were observed. These nanoformulations demonstrated ~95% entrapment efficiency with around 5% drug loading. Stability tests revealed that the NLCs remained stable for 6 months under storage conditions at 4 °C. In vitro release studies indicated sustained release over 24 h, following Higuchi and Korsmeyer–Peppas models for NLCs and FA NLCs, respectively. Additionally, an in vitro pH-stat lipolysis model exhibited a nearly fivefold increase in bioaccessibility compared to drug-loaded suspensions. The DOC–ERL-loaded formulations exhibited dose- and time-dependent cytotoxicity, revealing synergism at a 1:3 molar ratio in MDA-MB-231 and 4T1 cells, with combination indices of 0.35 and 0.37, respectively. Co-treatment with DOC–ERL-loaded FA NLCs demonstrated synergistic anticancer effects in various in vitro assays.

Multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii) is one of the major pathogens present in burn wound infections. Biofilm formation makes it further challenging to treat with clinically available antibiotics. In the current work, we isolated the A. baumannii-specific bacteriophages (BPABΦ1), loaded into the chitosan microparticles followed by dispersion in gel, and evaluated therapeutic efficacy against MDR A. baumannii clinical strains. Isolated BPABΦ1 were found to belong to the Corticoviridae family, with burst size 102.12 ± 2.65 PFUs per infected host cell. The BPABΦ1 loaded chitosan microparticles were evaluated for quality attributes viz. size, PDI, surface morphology, in vitro release, etc. The developed formulation exhibited excellent antibiofilm eradication potential in vitro and effective wound healing after topical application.

Triple-negative breast cancer is considered the most aggressive type of breast cancer among women and the lack of expressed receptors has made treatment options substantially limited. Recently, various types of nanoparticles have emerged as a therapeutic option against TNBC, to elevate the therapeutic efficacy of the existing chemotherapeutics. Among the various nanoparticles, lipid-based nanoparticles (LNPs) viz. liposomes, nanoemulsions, solid lipid nanoparticles, nanostructured lipid nanocarriers, and lipid–polymer hybrid nanoparticles are developed for cancer treatment which is well confirmed and documented. LNPs include various therapeutic advantages as compared to conventional therapy and other nanoparticles, including increased loading capacity, enhanced temporal and thermal stability, decreased therapeutic dose and associated toxicity, and limited drug resistance. In addition to these, LNPs overcome physiological barriers which provide increased accumulation of therapeutics at the target site. Extensive efforts by the scientific community could make some of the liposomal formulations the clinical reality; however, the relatively high cost, problems in scaling up the formulations, and delivery in a more targetable fashion are some of the major issues that need to be addressed. In the present review, we have compiled the state of the art about different types of LNPs with the latest advances reported for the treatment of TNBC in recent years, along with their clinical status and toxicity in detail.

Breast cancer is a heterogeneous disease which accounts globally for approximately 1 million new cases annually, wherein more than 200,000 of these cases turn out to be cases of triple-negative breast cancer (TNBC). TNBC is an aggressive and rare breast cancer subtype that accounts for 10–15% of all breast cancer cases. Chemotherapy remains the only therapy regimen against TNBC. However, the emergence of innate or acquired chemoresistance has hindered the chemotherapy used to treat TNBC. The data obtained from molecular technologies have recognized TNBC with various gene profiling and mutation settings that have helped establish and develop targeted therapies. New therapeutic strategies based on the targeted delivery of therapeutics have relied on the application of biomarkers derived from the molecular profiling of TNBC patients. Several biomarkers have been found that are targets for the precision therapy in TNBC, such as EGFR, VGFR, TP53, interleukins, insulin-like growth factor binding proteins, c-MET, androgen receptor, BRCA1, glucocorticoid, PTEN, ALDH1, etc. This review discusses the various candidate biomarkers identified in the treatment of TNBC along with the evidence supporting their use. It was established that nanoparticles had been considered a multifunctional system for delivering therapeutics to target sites with increased precision. Here, we also discuss the role of biomarkers in nanotechnology translation in TNBC therapy and management.

Exosomes are biological nanovesicles that are intrinsically loaded with thousands of biomacromolecules and are principally responsible for cell-to-cell communication. Inspired by the natural payload, they have been extensively investigated as drug delivery vehicles; however, the drug distribution, whether into or onto exosomes, is still debatable. In the present work, we have tried to investigate it systemically by selecting 5-fluorouracil (5-FU) (hydrophilic) and paclitaxel (PAC) (hydrophobic), drugs with very different physicochemical characteristics, for the loading to the exosomes. Exosomes were obtained from bovine milk, and the drugs were loaded using three different methods: incubation, sonication, and triton x-100. The particle size was found to be approximately 100 nm in all the cases; however, the highest drug loading was found in the sonication method. Fluorescence spectrophotometer, EDX analysis, EDX mapping, XPS, and XRD analysis indicated the possible presence of more drugs over the surface in the case of the incubation method. Drugs loaded by the sonication method had more controlled release than simple incubation and triton x-100. The method of drug loading had an insignificant effect on the cytotoxicity while in line with our previous observation, the combination (PAC and 5-FU) exhibited synergism as evidenced by ROS assay, colony formation assay, and mitochondrial membrane potential assay. Graphical Abstract

Repurposing drugs offers several advantages, including reduced time and cost compared to developing new drugs from scratch. It leverages existing knowledge about drug safety, dosage, and pharmacokinetics, expediting the process of clinical trials and regulatory approval. Dihydroartemisinin (DHA) is a semi-synthetic and active metabolite of all artemisinin molecules and is FDA-approved for the treatment of malaria. Apart from having anti-malarial properties, DHA also possesses anticancer properties. However, its pharmacological actions are limited by toxicity and solubility problems. To overcome these challenges and enhance its anticancer effectiveness, we designed an exosomal formulation of DHA. We isolated exosomes from bovine milk using differential ultracentrifugation and loaded DHA using sonication. Scanning and transition electron microscopy revealed a size of roughly 100 nm, with a spherical shape. Furthermore, in pH 7.4 and 5.5, the exosomes exhibited burst release followed by sustained release. Multiple in vitro cell culture tests demonstrated that Exo-DHA exhibited enhanced anticancer activity, including cytotoxicity, cellular uptake, generation of reactive oxygen species (ROS), disruption of mitochondrial membrane potential, and inhibition of colony formation. Additional evidence supporting Exo-DHA's anti-migration ability came from transwell migration and scratch assays. Based on these results, it was concluded that the anticancer efficacy of DHA was improved when loaded into bovine milk-derived exosomes. While the in vitro results are encouraging, more in vivo testing in suitable animal models and biochemical marker analysis are warranted. Graphical Abstract

Klebsiella pneumoniae is regarded as one of the most profound bacteria isolated from the debilitating injuries caused by burn wounds. In addition, the multidrug resistance (MDR) and biofilm formation make treating burn patients with clinically available antibiotics difficult. Bacteriophage therapy has been proven an effective alternative against biofilm-mediated wound infections caused by MDR bacterial strains. In the current study, the bacteriophage (BPKPФ1) against MDR Klebsiella pneumoniae was isolated and loaded into the chitosan microparticles (CHMPs), which was later incorporated into the Sepineo P 600 to convert into a gel (BPKPФ1-CHMP-gel). BPKPФ1 was characterized for lytic profile, morphological class, and burst size, which revealed that the BPKPФ1 belongs to the family Siphoviridae . Moreover, BPKPФ1 exhibited a narrow host range with 128 PFU/host cell of burst size. The BPKPФ1-loaded CHMPs showed an average particle size of  1.96 ± 0.51 μm, zeta potential 32.16 ± 0.41 mV, and entrapment efficiency in the range of 82.44 ± 1.31%. Further, the in vitro antibacterial and antibiofilm effectiveness of BPKPФ1-CHMPs-gel were examined. The in vivo potential of the BPKPФ1-CHMPs-gel was assessed using a rat model with MDR Klebsiella pneumoniae infected burn wound, which exhibited improved wound contraction (89.22 ± 0.48%) in 28 days with reduced inflammation, in comparison with different controls. Data in hand suggest the potential of bacteriophage therapy to be developed as personalized therapy in case of difficult-to-treat bacterial infections. Graphical abstract