Personalized Versus Precision Nanomedicine for Treatment of Ovarian Cancer.

The response to treatment is substantially varied between individual patients with ovarian cancer. However, chemotherapy treatment plans rarely pay sufficient attention to the mentioned factors. Instead, standardized treatment protocols are usually employed for most ovarian cancer patients. Variations in an individual's sensitivity to drugs significantly limit the effectiveness of treatment in some patients and lead to severe toxicities in others. In the present investigation, a nanotechnology-based approach for personalized treatment of ovarian carcinoma (the most lethal type of gynecological cancer) constructed on the individual genetic profile of the patient's tumor is developed and validated. The expression of predefined genes and proteins is analyzed for each patient sample. Finally, a mixture of the complex nanocarrier-based targeted delivery system containing drug(s)/siRNA(s)/targeted peptide is selected from the pre-synthesized bank and tested in vivo on murine cancer model using cancer cells isolated from tumors of each patient. Based on the results of the present study, an innovative approach and protocol for personalized treatment of ovarian cancer are suggested and evaluated. The results of the present study clearly show the advantages and perspectives of the proposed individual treatment approach.

Synergistic antitumor effect of liposomal-based formulations of olaparib and topotecan in primary epithelial ovarian cancer cells.

BACKGROUND: Olaparib is a PARP inhibitor inducing synthetic lethality in tumors with deficient homologous recombination (HRD) caused by BRCA1/2 mutations. The FDA has approved monotherapy for first-line platinum-sensitive, recurrent high-grade epithelial ovarian cancer. Combination therapy alongside DNA-damaging therapeutics is a promising solution to overcome the limited efficacy in patients with HRD. The present study was designed to develop topotecan- and olaparib-loaded liposomes (TLL and OLL) and assess the effectiveness of their combination in patient-derived ovarian cancer samples. METHODS: We used HEOC, four clear-cell tumors (EOC 1-4), malignant ascites, and an OCI-E1p endometrioid primary ovarian cancer cell line and performed NGS analysis of BRCA1/2 mutation status. Antiproliferative activity was determined with the MTT assay. The Chou-Talalay algorithm was used to investigate the in vitro pharmacodynamic interactions of TLLs and OLLs. RESULTS: The OLL showed significantly higher efficacy in all ovarian cancer types with wild-type BRCA1/2 than a conventional formulation, suggesting potential for increased in vivo efficacy. The TLL revealed substantially higher toxicity to EOC 1, EOC 3, ascites and lower toxicity to HEOC than the standard formulation, suggesting better therapeutic efficacy and safety profile. The combination of studied compounds showed a higher reduction in cell viability than drugs used individually, demonstrating a synergistic antitumor effect at most of the selected concentrations. CONCLUSIONS: The concentration-dependent response of different ovarian cancer cell types to combination therapy confirms the need for in vitro optimization to maximize drug cytotoxicity. The OLL and TLL combination is a promising formulation for further animal studies, especially for eliminating epithelial ovarian cancer with wild-type BRCA1/2.

Nanotechnology-Based Strategy for Enhancing Therapeutic Efficacy in Pancreatic Cancer: Receptor-Targeted Drug Delivery by Somatostatin Analog.

A novel nanotechnology-based drug delivery system (DDS) targeted at pancreatic cancer cells was developed, characterized, and tested. The system consisted of liposomes as carriers, an anticancer drug (paclitaxel) as a chemotherapeutic agent, and a modified synthetic somatostatin analog, 5-pentacarbonyl-octreotide, a ligand for somatostatin receptor 2 (SSTR2), as a targeting moiety for pancreatic cancer. The cellular internalization, cytotoxicity, and antitumor activity of the DDS were tested in vitro using human pancreatic ductal adenocarcinoma (PDAC) cells with different expressions of the targeted SSTR2 receptors, and in vivo on immunodeficient mice bearing human PDAC xenografts. The targeted drug delivery system containing paclitaxel exhibited significantly enhanced cytotoxicity compared to non-targeted DDS, and this efficacy was directly related to the levels of SSTR2 expression. It was found that octreotide-targeted DDS proved exceptionally effective in suppressing the growth of PDAC tumors. This study underscores the potential of octreotide-targeted liposomal delivery systems to enhance the therapeutic outcomes for PDAC compared with non-targeted liposomal DDS and Paclitaxel-Cremophor® EL, suggesting a promising avenue for future cancer therapy innovations.

Nanotechnology-Based Nucleic Acid Vaccines for Treatment of Ovarian Cancer.

Anticancer vaccines represent a promising approach for effective treatment of cancer and along with recent advantages of nucleic acid-based vaccines for other diseases form a prospective and potentially efficacious direction of the research, development and clinical applications. Despite the ongoing several clinical trials of mRNA vaccines for the treatment of various types of cancer, to-date no cancer vaccines were approved by the US Food and Drug Administration. The present review analyzes and summarizes major approaches for treating of different forms of ovarian cancer including mRNA-based vaccines as well as nanotechnology-based approaches for their delivery.

On the plasticizing properties of divalproex sodium: physicochemical and spectroscopic characterization studies.

The objective of the research was to demonstrate the plasticization properties of divalproex sodium, due to its component-valproic acid, on ethyl cellulose, which could prove beneficial for film fabrications or hot melt extrusion based formulations. Films containing 10-50% w/w (DVS/EC) as dry weight were prepared using solvent evaporation method and characterized using texture analyzer, hybrid rheometer, differential scanning calorimetry, thermogravimetry, X-ray diffractometry, polarized microscopy, FTIR, and Raman spectroscopy. It was found that there was a decrease in average peak load, melt viscosity, and glass transition temperature (Tg) while increase in elongation, with increase in concentration of DVS in the films. These results demonstrate the plasticization tendency of DVS on EC, which was attributed to the presence of valproic acid (fatty acid) in DVS. XRD studies showed amorphous nature of the films; however, polarized microscopy revealed the presence of scattered undissolved sodium valproate crystals. The presence of a single Tg established complete miscibility between valproic acid and EC. Films showed reasonable physical stability (similar Tg) at 45 °C/75% RH for 2 weeks (open condition), attributable to the similar solubility parameters of DVS and EC. FTIR and Raman spectroscopy results proved the presence of hydrogen bonding between DVS and EC.

Combinatorial treatment of idiopathic pulmonary fibrosis using nanoparticles with prostaglandin E and siRNA(s).

Inhalation delivery of prostaglandin E (PGE2) in combination with selected siRNA(s) was proposed for the efficient treatment of idiopathic pulmonary fibrosis (IPF). Nanostructured lipid carriers (NLC) were used as a delivery system for PGE2 with and without siRNAs targeted to MMP3, CCL12, and HIF1Alpha mRNAs. The model of IPF was developed in SKH1 mice by intratracheal administration of bleomycin at a dose of 1.5U/kg. Results showed that NLC-PGE2 in combination with three siRNAs delivered locally to the lungs by inhalation markedly reduced mouse body mass, substantially limited hydroxyproline content in the lungs and disturbances of the mRNAs and protein expression, restricted lung tissue damage and prevented animal mortality. Our data provide evidence that IPF can be effectively treated by inhalation of the NLC-PGE2 in combination with siRNAs delivered locally into the lungs. This effect could not be achieved by using NLC containing just PGE2 or siRNA(s) alone.

Biodegradable Janus nanoparticles for local pulmonary delivery of hydrophilic and hydrophobic molecules to the lungs.

The aim of the present work is to synthesize, characterize, and test self-assembled anisotropic or Janus particles designed to load anticancer drugs for lung cancer treatment by inhalation. The particles were synthesized using binary mixtures of biodegradable and biocompatible materials. The particles did not demonstrate cyto- and genotoxic effects. Janus particles were internalized by cancer cells and accumulated both in the cytoplasm and nuclei. After inhalation delivery, nanoparticles accumulated preferentially in the lungs of mice and retained there for at least 24 h. Two drugs or other biologically active components with substantially different aqueous solubility can be simultaneously loaded in two-phases (polymer-lipid) of these nanoparticles. In the present proof-of-concept investigation, the particles were loaded with two anticancer drugs: doxorubicin and curcumin as model anticancer drugs with relatively high and low aqueous solubility, respectively. However, there are no obstacles for loading any hydrophobic or hydrophilic chemical agents. Nanoparticles with dual load were used for their local inhalation delivery directly to the lungs of mice with orthotopic model of human lung cancer. In vivo experiments showed that the selected nanoparticles with two anticancer drugs with different mechanisms of action prevented progression of lung tumors. It should be stressed that anticancer effects of the combined treatment with two anticancer drugs loaded in the same nanoparticle significantly exceeded the effect of either drug loaded in similar nanoparticles alone.

Dendritic silica nanomaterials (KCC-1) with fibrous pore structure possess high DNA adsorption capacity and effectively deliver genes in vitro.

The pore size and pore structure of nanoporous materials can affect the materials' physical properties, as well as potential applications in different areas, including catalysis, drug delivery, and biomolecular therapeutics. KCC-1, one of the newest members of silica nanomaterials, possesses fibrous, large pore, dendritic pore networks with wide pore entrances, large pore size distribution, spacious pore volume and large surface area--structural features that are conducive for adsorption and release of large guest molecules and biomacromolecules (e.g., proteins and DNAs). Here, we report the results of our comparative studies of adsorption of salmon DNA in a series of KCC-1-based nanomaterials that are functionalized with different organoamine groups on different parts of their surfaces (channel walls, external surfaces or both). For comparison the results of our studies of adsorption of salmon DNA in similarly functionalized, MCM-41 mesoporous silica nanomaterials with cylindrical pores, some of the most studied silica nanomaterials for drug/gene delivery, are also included. Our results indicate that, despite their relatively lower specific surface area, the KCC-1-based nanomaterials show high adsorption capacity for DNA than the corresponding MCM-41-based nanomaterials, most likely because of KCC-1's large pores, wide pore mouths, fibrous pore network, and thereby more accessible and amenable structure for DNA molecules to diffuse through. Conversely, the MCM-41-based nanomaterials adsorb much less DNA, presumably because their outer surfaces/cylindrical channel pore entrances can get blocked by the DNA molecules, making the inner parts of the materials inaccessible. Moreover, experiments involving fluorescent dye-tagged DNAs suggest that the amine-grafted KCC-1 materials are better suited for delivering the DNAs adsorbed on their surfaces into cellular environments than their MCM-41 counterparts. Finally, cellular toxicity tests show that the KCC-1-based materials are biocompatible. On the basis of these results, the fibrous and porous KCC-1-based nanomaterials can be said to be more suitable to carry, transport, and deliver DNAs and genes than cylindrical porous nanomaterials such as MCM-41.

Tumor-targeted responsive nanoparticle-based systems for magnetic resonance imaging and therapy.

PURPOSE: Design and synthesis of a tumor responsive nanoparticle-based system for imaging and treatment of various cancers. METHODS: Manganese oxide nanoparticles (Mn3O4 NPs) were synthesized and modified with LHRH targeting peptide or anti-melanoma antibodies (cancer targeting moieties) and a MMP2 cleavable peptide (a possible chemotactic factor). Nanostructured lipid carriers (NLCs) were used to entrap the BRAF inhibitor, vemurafenib, and enhance cytotoxicity of the drug. Size distribution, stability, drug entrapment, cytotoxicity and genotoxicity of synthesized nanoparticles were studied in vitro. Enhancement of MRI signal by nanoparticles and their body distribution were examined in vivo on mouse models of melanoma, ovarian and lung cancers. RESULTS: Uniform, stable cancer-targeted nanoparticles (PEGylated water-soluble Mn3O4 NPs and NLCs) were synthesized. No signs of cyto-,genotoxicity and DNA damage were detected for nanoparticles that do not contain an anticancer drug. Entrapment of vemurafenib into nanoparticles significantly enhanced drug toxicity in cancer cells with targeted V600E mutation. The developed nanoparticles containing LHRH and MMP2 peptides showed preferential accumulation in primary and metastatic tumors increasing the MRI signal in mice with melanoma, lung and ovarian cancers. CONCLUSIONS: The proposed nanoparticle-based systems provide the foundation for building an integrated MRI diagnostic and therapeutic approach for various types of cancer.

Targeted Nanoparticle-Based Diagnostic and Treatment Options for Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest cancers, presents significant challenges in diagnosis and treatment due to its aggressive, metastatic nature and lack of early detection methods. A key obstacle in PDAC treatment is the highly complex tumor environment characterized by dense stroma surrounding the tumor, which hinders effective drug delivery. Nanotechnology can offer innovative solutions to these challenges, particularly in creating novel drug delivery systems for existing anticancer drugs for PDAC, such as gemcitabine and paclitaxel. By using customization methods such as incorporating conjugated targeting ligands, tumor-penetrating peptides, and therapeutic nucleic acids, these nanoparticle-based systems enhance drug solubility, extend circulation time, improve tumor targeting, and control drug release, thereby minimizing side effects and toxicity in healthy tissues. Moreover, nanoparticles have also shown potential in precise diagnostic methods for PDAC. This literature review will delve into targeted mechanisms, pathways, and approaches in treating pancreatic cancer. Additional emphasis is placed on the study of nanoparticle-based delivery systems, with a brief mention of those in clinical trials. Overall, the overview illustrates the significant advances in nanomedicine, underscoring its role in transcending the constraints of conventional PDAC therapies and diagnostics.

Liposomal Formulations of Anti-Alzheimer Drugs and siRNA for Nose-to-Brain Delivery: Design, Safety and Efficacy In Vitro.

ß-site amyloid precursor protein cleaving enzyme (BACE1) represents a key target for Alzheimer's disease (AD) therapy because it is essential for producing the toxic amyloid ß (Aß) peptide that plays a crucial role in the disease's development. BACE1 inhibitors are a promising approach to reducing Aß levels in the brain and preventing AD progression. However, systemic delivery of such inhibitors to the brain demonstrates limited efficacy because of the presence of the blood-brain barrier (BBB). Nose-to-brain (NtB) delivery has the potential to overcome this obstacle. Liposomal drug delivery systems offer several advantages over traditional methods for delivering drugs and nucleic acids from the nose to the brain. The current study aims to prepare, characterize, and evaluate in vitro liposomal forms of donepezil, memantine, BACE-1 siRNA, and their combination for possible treatment of AD via NtB delivery. All the liposomal formulations were prepared using the rotary evaporation method. Their cellular internalization, cytotoxicity, and the suppression of beta-amyloid plaque and other pro-inflammatory cytokine expressions were studied. The Calu-3 Transwell model was used as an in vitro system for mimicking the anatomical and physiological conditions of the nasal epithelium and studying the suitability of the proposed formulations for possible NtB delivery. The investigation results show that liposomes provided the effective intracellular delivery of therapeutics, the potential to overcome tight junctions in BBB, reduced beta-amyloid plaque accumulation and pro-inflammatory cytokine expression, supporting the therapeutic potential of our approach.

Inhibition of lung tumor growth by complex pulmonary delivery of drugs with oligonucleotides as suppressors of cellular resistance.

Development of cancer cell resistance, low accumulation of therapeutic drug in the lungs, and severe adverse treatment side effects represent main obstacles to efficient chemotherapy of lung cancer. To overcome these difficulties, we propose inhalation local delivery of anticancer drugs in combination with suppressors of pump and nonpump cellular resistance. To test this approach, nanoscale-based delivery systems containing doxorubicin as a cell death inducer, antisense oligonucleotides targeted to MRP1 mRNA as a suppressor of pump resistance and to BCL2 mRNA as a suppressor of nonpump resistance, were developed and examined on an orthotopic murine model of human lung carcinoma. The experimental results show high antitumor activity and low adverse side effects of proposed complex inhalatory treatment that cannot be achieved by individual components applied separately. The present work potentially contributes to the treatment of lung cancer by describing a unique combinatorial local inhalation delivery of drugs and suppressors of pump and nonpump cellular resistance.

Nanotechnology-Based RNA Vaccines: Fundamentals, Advantages and Challenges.

Over the past decades, many drugs based on the use of nanotechnology and nucleic acids have been developed. However, until recently, most of them remained at the stage of pre-clinical development and testing and did not find their way to the clinic. In our opinion, the main reason for this situation lies in the enormous complexity of the development and industrial production of such formulations leading to their high cost. The development of nanotechnology-based drugs requires the participation of scientists from many and completely different specialties including Pharmaceutical Sciences, Medicine, Engineering, Drug Delivery, Chemistry, Molecular Biology, Physiology and so on. Nevertheless, emergence of coronavirus and new vaccines based on nanotechnology has shown the high efficiency of this approach. Effective development of vaccines based on the use of nucleic acids and nanomedicine requires an understanding of a wide range of principles including mechanisms of immune responses, nucleic acid functions, nanotechnology and vaccinations. In this regard, the purpose of the current review is to recall the basic principles of the work of the immune system, vaccination, nanotechnology and drug delivery in terms of the development and production of vaccines based on both nanotechnology and the use of nucleic acids.

Plant-derived single domain COVID-19 antibodies.

Data show a decrease in the risk of hospitalization and death from COVID-19. To date, global vaccinations for SARS-CoV-2 protections are underway, but additional treatments are urgently needed to prevent and cure infection among naïve and even vaccinated people. Neutralizing monoclonal antibodies are very promising for prophylaxis and therapy of SARS-CoV-2 infections. However, traditional large-scale methods of producing such antibodies are slow, extremely expensive and possess a high risk of contamination with viruses, prions, oncogenic DNA and other pollutants. The present study is aimed at developing an approach of producing monoclonal antibodies (mAbs) against SARS-CoV-2 spike (S) protein in plant systems which offers unique advantages, such as the lack of human and animal pathogens or bacterial toxins, relatively low-cost manufacturing, and ease of production scale-up. We selected a single N-terminal domain functional camelid-derived heavy (H)-chain antibody fragments (VHH, AKA nanobodies) targeted to receptor binding domain of SARS-CoV-2 spike protein and developed methods of their rapid production using transgenic plants and plant cell suspensions. Isolated and purified plant-derived VHH antibodies were compared with mAbs produced in traditional mammalian and bacterial expression systems. It was found that plant generated VHH using the proposed methods of transformation and purification possess the ability to bind to SARS-CoV-2 spike protein comparable to that of monoclonal antibodies derived from bacterial and mammalian cell cultures. The results of the present studies confirm the visibility of producing monoclonal single-chain antibodies with a high ability to bind the targeted COVID-19 spike protein in plant systems within a relatively shorter time span and at a lower cost when compared with traditional methods. Moreover, similar plant biotechnology approaches can be used for producing monoclonal neutralizing antibodies against other types of viruses.

Inhibition of Mtorc1/2 and DNA-PK via CC-115 Synergizes with Carboplatin and Paclitaxel in Lung Squamous Cell Carcinoma.

Only a small percentage (<1%) of patients with late-stage lung squamous cell carcinoma (LUSC) are eligible for targeted therapy. Because PI3K/AKT/mTOR signaling, particularly Phosphatidylinositol 3-kinase CA (PIK3CA), is dysregulated in two-thirds of LUSC, and DNA damage response pathways are enriched in LUSC, we tested whether CC-115, a dual mTORC1/2 and DNA-PK inhibitor, sensitizes LUSC to chemotherapy. We demonstrate that CC-115 synergizes with carboplatin in six of 14 NSCLC cell lines, primarily PIK3CA-mutant LUSC. Synergy was more common in cell lines that had decreased basal levels of activated AKT and DNA-PK, evidenced by reduced P-S473-AKT, P-Th308-AKT, and P-S2056-DNA-PKcs. CC-115 sensitized LUSC to carboplatin by inhibiting chemotherapy-induced AKT activation and maintaining apoptosis, particularly in PIK3CA-mutant cells lacking wild-type (WT) TP53. In addition, pathway analysis revealed that enrichments in the IFNα and IFNγ pathways were significantly associated with synergy. In multiple LUSC patient-derived xenograft and cell line tumor models, CC-115 plus platinum-based doublet chemotherapy significantly inhibited tumor growth and increased overall survival as compared with either treatment alone at clinically relevant dosing schedules. IHC and immunoblot analysis of CC-115-treated tumors demonstrated decreased P-Th308-AKT, P-S473-AKT, P-S235/236-S6, and P-S2056-DNA-PKcs, showing direct pharmacodynamic evidence of inhibited PI3K/AKT/mTOR signaling cascades. Because PI3K pathway and DNA-PK inhibitors have shown toxicity in clinical trials, we assessed toxicity by examining weight and numerous organs in PRKDC-WT mice, which demonstrated that the combination treatment does not exacerbate the clinically accepted side effects of standard-of-care chemotherapy. This preclinical study provides strong support for the further investigation of CC-115 plus chemotherapy in LUSC.

Recent Developments on Therapeutic and Diagnostic Approaches for COVID-19.

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made a serious public health threat worldwide with millions of people at risk in a growing number of countries. Though there are no clinically approved antiviral drugs and vaccines for COVID-19, attempts are ongoing for clinical trials of several known antiviral drugs, their combination, as well as development of vaccines in patients with confirmed COVID-19. This review focuses on the latest approaches to diagnostics and therapy of COVID-19. We have summarized recent progress on the conventional therapeutics such as antiviral drugs, vaccines, anti-SARS-CoV-2 antibody treatments, and convalescent plasma therapy which are currently under extensive research and clinical trials for the treatment of COVID-19. The developments of nanoparticle-based therapeutic and diagnostic approaches have been also discussed for COVID-19. We have assessed recent literature data on this topic and made a summary of current development and future perspectives.

Multifunctional Lipid-Based Nanoparticles for Codelivery of Anticancer Drugs and siRNA for Treatment of Non-Small Cell Lung Cancer with Different Level of Resistance and EGFR Mutations.

Resistance to chemotherapy, enhanced proliferation, invasion, angiogenesis, and metastasis (RPIAM) represent major obstacles that limit the efficacy of cancer treatment especially in advanced stages of cancer. Overcoming or suppressing RPIAM can dramatically improve the treatment outcome. Non-small cell lung cancer (NSCLC) is frequently diagnosed in an advanced stage and often possesses intrinsic resistance to chemotherapy accompanied by the fast development of acquired resistance during the treatment. Oncogenic receptor tyrosine kinases (TKs), specifically epidermal growth factor (EGF) TKs, play an important role in the activation of MAPK/PI3K/Akt/STAT pathways, finally leading to the development of RPIAM. However, the suppression of EGF-TK by different drugs is limited by various defensive mechanisms and mutations. In order to effectively prevent the development of RPIAM in NSCLC, we formulated and tested a multicomponent and multifunctional cancer targeted delivery system containing Nanostructured Lipid Carriers (NLCs) as vehicles, luteinizing hormone release hormone (LHRH) as a cancer targeting moiety, EFG-TK inhibitor gefitinib and/or paclitaxel as anticancer drug(s), siRNA targeted to EGF receptor (EGFR) mRNA as a suppressor of EGF receptors, and an imaging agent (rhodamine) for the visualization of cancer cells. Experimental data obtained show that this complex delivery system possesses significantly enhanced anticancer activity that cannot be achieved by individual components applied separately.

Nanotherapeutics for Nose-to-Brain Drug Delivery: An Approach to Bypass the Blood Brain Barrier.

Treatment of neurodegenerative diseases or other central nervous system (CNS) disorders has always been a significant challenge. The nature of the blood-brain barrier (BBB) limits the penetration of therapeutic molecules to the brain after oral or parenteral administration, which, in combination with hepatic metabolism and drug elimination and inactivation during its journey in the systemic circulation, decreases the efficacy of the treatment, requires high drug doses and often induces adverse side effects. Nose-to-brain drug delivery allows the direct transport of therapeutic molecules by bypassing the BBB and increases drug concentration in the brain. The present review describes mechanisms of nose-to-brain drug delivery and discusses recent advances in this area with especial emphasis on nanotechnology-based approaches.

Multifunctional and stimuli-responsive nanocarriers for targeted therapeutic delivery.

INTRODUCTION: Nanocarrier-based delivery systems offer multiple benefits to overcome limitations of the traditional drug dosage forms, such as protection of the drug, enhanced bioavailability, targeted delivery to disease site, etc. Nanocarriers have exhibited tremendous successes in targeted delivery of therapeutics to the desired tissues and cells with improved bioavailability, high drug loading capacity, enhanced intracellular delivery, and better therapeutic effect. A specific design of stimuli-responsive nanocarriers allows for changing their structural and physicochemical properties in response to exogenous and endogenous stimuli. These nanocarriers show a promise in site specific controlled release of therapeutics under certain physiological conditions or external stimuli. AREAS COVERED: This review highlights recent progresses on the multifunctional and stimuli-sensitive nanocarriers for targeted therapeutic drug delivery applications. EXPERT OPINION: The progress from single functional to multifunctional nanocarriers has shown tremendous potential for targeted delivery of therapeutics. On our opinion, the future of targeted delivery of drugs, nucleic acids, and other substances belongs to the site-targeted multifunctional and stimuli-based nanoparticles with controlled release. Targeting of nanocarriers to the disease site enhance the efficacy of the treatment by delivering more therapeutics specifically to the affected cells and substantially limiting adverse side effects upon healthy organs, tissues, and cells.