Tumor microenvironment reprogramming by nanomedicine to enhance the effect of tumor immunotherapy

With the rapid development of the fields of tumor biology and immunology, tumor immunotherapy has been used in clinical practice and has demonstrated significant therapeutic potential, particularly for treating tumors that do not respond to standard treatment options. Despite its advances, immunotherapy still has limitations, such as poor clinical response rates and differences in individual patient responses, largely because tumor tissues have strong immunosuppressive microenvironments. Many tumors have a tumor microenvironment (TME) that is characterized by hypoxia, low pH, and substantial numbers of immunosuppressive cells, and these are the main factors limiting the efficacy of antitumor immunotherapy. The TME is crucial to the occurrence, growth, and metastasis of tumors. Therefore, numerous studies have been devoted to improving the effects of immunotherapy by remodeling the TME. Effective regulation of the TME and reversal of immunosuppressive conditions are effective strategies for improving tumor immunotherapy. The use of multidrug combinations to improve the TME is an efficient way to enhance antitumor immune efficacy. However, the inability to effectively target drugs decreases therapeutic effects and causes toxic side effects. Nanodrug delivery carriers have the advantageous ability to enhance drug bioavailability and improve drug targeting. Importantly, they can also regulate the TME and deliver large or small therapeutic molecules to decrease the inhibitory effect of the TME on immune cells. Therefore, nanomedicine has great potential for reprogramming immunosuppressive microenvironments and represents a new immunotherapeutic strategy. Therefore, this article reviews strategies for improving the TME and summarizes research on synergistic nanomedicine approaches that enhance the efficacy of tumor immunotherapy.

Advanced nanomedicines and immunotherapeutics to treat respiratory diseases especially COVID-19 induced thrombosis

Immunotherapy and associated immune regulation strategies gained huge attraction in order to be utilized for treatment and prevention of respiratory diseases.Engineering specifically nanomedicines can be used to regulate host immunity in lungs in the case of respiratory diseases including coronavirus disease 2019(COVID-19)infection.COVID-19 causes pulmonary embolisms,thus new therapeutic options are required to target thrombosis,as conventional treatment options are either not effective due to the complexity of the immunethrombosis pathophysiology.In this review,we discuss regulation of immune response in respiratory diseases especially COVID-19.We further discuss thrombosis and provide an overview of some antithrombotic nanoparticles,which can be used to develop nanomedicine against thrombo-inflammation induced by COVID-19 and other respiratory infectious diseases.We also elaborate the importance of immunomodulatory nanomedicines that can block pro-inflammatory signalling pathways,and thus can be recommended to treat respiratory infectious diseases.

Nanomedicine-boosting icaritin-based immunotherapy of advanced hepatocellular carcinoma

Traditional treatments for advanced hepatocellular carcinoma(HCC),such as surgical resection,transplantation,radiofrequency ablation,and chemotherapy are unsatisfactory,and therefore the exploration of powerful therapeutic strategies is urgently needed.Immunotherapy has emerged as a promising strategy for advanced HCC treatment due to its minimal side effects and long-lasting therapeutic memory effects.Recent studies have demonstrated that icaritin could serve as an immunomodulator for effective immunotherapy of advanced HCC.Encouragingly,in 2022,icaritin soft capsules were approved by the National Medical Products Administration(NMPA)of China for the immunotherapy of advanced HCC.However,the therapeutic efficacy of icaritin in clinical practice is impaired by its poor bioavailability and unfavorable in vivo delivery efficiency.Recently,functionalized drug delivery systems including stimuli-responsive nanocarriers,cell membrane-coated nanocarriers,and living cell-nanocarrier systems have been designed to overcome the shortcomings of drugs,including the low bioavailability and limited delivery efficiency as well as side effects.Taken together,the development of icaritin-based nanomedicines is expected to further improve the immunotherapy of advanced HCC.Herein,we compared the different preparation methods for icaritin,interpreted the HCC immune microenvironment and the mechanisms underlying icaritin for treatment of advanced HCC,and discussed both the design of icaritin-based nanomedicines with high icaritin loading and the latest progress in icaritinbased nanomedicines for advanced HCC immunotherapy.Finally,the prospects to promote further clinical translation of icaritin-based nanomedicines for the immunotherapy of advanced HCC were proposed.

Nanomedicine-based multimodal therapies:Recent progress and perspectives in colon cancer

Colon cancer has attracted much attention due to its annually increasing incidence.Conventional chemotherapeutic drugs are unsatisfactory in clinical application because of their lack of targeting and severe toxic side effects.In the past decade,nanomedicines with multimodal therapeutic strategies have shown potential for colon cancer because of their enhanced permeability and retention,high accumulation at tumor sites,co-loading with different drugs,and combination of various therapies.This review summarizes the advances in research on various nanomedicine-based therapeutic strategies including chemotherapy,radiotherapy,phototherapy(photothermal therapy and photodynamic therapy),chemodynamic therapy,gas therapy,and immunotherapy.Additionally,the therapeutic mechanisms,limitations,improvements,and future of the above therapies are discussed.

Importance of Standardizing Analytical Characterization Methodology for Improved Reliability of the Nanomedicine Literature

Understanding the interaction between biological structures and nanoscale technologies,dubbed the nano-bio interface,is required for successful development of safe and efficient nanomedicine products.The lack of a universal reporting system and decentralized methodologies for nanomaterial characterization have resulted in a low degree of reliability and reproducibility in the nanomedicine literature.As such,there is a strong need to establish a characterization system to support the reproducibility of nanoscience data particularly for studies seeking clinical translation.Here,we discuss the existing key standards for addressing robust characterization of nanomaterials based on their intended use in medical devices or as pharmaceuticals.We also discuss the challenges surrounding implementation of such standard protocols and their implication for translation of nanotechnology into clinical practice.We,however,emphasize that practical implementation of standard protocols in experimental laboratories requires long-term planning through integration of stakeholders including institutions and funding agencies.

Potential prospects of nanomedicine for targeted therapeutics in inflammatory bowel diseases

Inflammatory bowel diseases (IBDs) such as Crohn's disease are highly debilitating. There are inconsistencies in response to and side effects in the current conventional medications, failures in adequate drug delivery, and the lack of therapeutics to offer complete remission in the presently available treatments of IBD. This suggests the need to explore beyond the horizons of conventional approaches in IBD therapeutics. This review examines the arena of the evolving IBD nanomedicine, studied so far in animal and in vitro models, before comprehensive clinical testing in humans. The investigations carried out so far in IBD models have provided substantial evidence of the nanotherapeutic approach as having the potential to overcome some of the current drawbacks to conventional IBD therapy. We analyze the pros and cons of nanotechnology in IBD therapies studied in different models, aimed at different targets and mechanisms of IBD pathogenesis, in an attempt to predict its possible impact in humans.

The endocytosis and intracellular fate of nanomedicines: Implication for rational design

Nanomedicines employ multiple endocytic pathways to enter cells.Their following fate is interesting,but it is not sufficient understood currently.This review introduces the endocytic pathways,presents new technologies to confirm the specific endocytic pathways and discusses factors for pathway selection.In addition,some intriguing implication about nanomedicine design based on endocytosis will also be discussed at the end.This review may provide new thoughts for the design of novel multifunctional nanomedicines.

Multimodality imaging in nanomedicine and nanotheranostics

Accurate diagnosis of tumors needs much detailed information. However, available single imaging modality cannot provide complete or comprehensive data. Nanomedicine is the application of nanotechnology to medicine, and multimodality imaging based on nanoparticles has been receiving extensive attention. This new hybrid imaging technology could provide complementary information from different imaging modalities using only a single injection of contrast agent. In this review, we introduce recent developments in multifunctional nanoparticles and their biomedical applications to multimodal imaging and theragnosis as nanomedicine. Most of the reviewed studies are based on the intrinsic properties of nanoparticles and their application in clinical imaging technology. The imaging techniques include positron emission tomography, single-photon emission computed tomography, computerized tomography, magnetic resonance imaging, optical imaging, and ultrasound imaging.

Overcoming the cellular barriers and beyond: Recent progress on cell penetrating peptide modified nanomedicine in combating physiological and pathological barriers

The complex physiological and pathological conditions form barriers against efficient drug delivery.Cell penetrating peptides(CPPs),a class of short peptides which translocate drugs across cell membranes with various mechanisms,provide feasible solutions for efficient delivery of biologically active agents to circumvent biological barriers.After years of development,the function of CPPs is beyond cell penetrating.Multifunctional CPPs with bioactivity or active targeting capacity have been designed and successfully utilized in delivery of various cargoes against tumor,myocardial ischemia,ocular posterior segment disorders,etc.In this review,we summarize recent progress in CPP-functionalized nano-drug delivery systems to overcome the physiological and pathological barriers for the applications in cardiology,ophtalmology,mucus,neurology and cancer,etc.We also highlight the prospect of clinical translation of CPP-functionalized drug delivery systems in these areas.

Nanomedicine potentiates mild photothermal therapy for tumor ablation

The booming photothermal therapy(PTT)has achieved great progress in non-invasive oncotherapy,and paves a novel way for clinical oncotherapy.Of note,mild temperature PTT(mPTT)of 42–45°C could avoid treatment bottleneck of the traditional PTT,including nonspecific injury to normal tissues,vasculature and host antitumor immunity.However,cancer cells can resist mPTT via heat shock response and autophagy,thus leading to insufficient mPTT monotherapy to ablate tumor.To overcome the deficient antitumor efficacy caused by thermo-resistance of cancer cells and mono mPTT,synergistic therapies towards cancer cells have been conducted with mPTT.This review summarizes the recent advances in nanomedicine-potentiated mPTT for cancer treatment,including strategies for enhanced single-mode mPTT and mPTT plus synergistic therapies.Moreover,challenges and prospects for clinical translation of nanomedicine-potentiated mPTT are discussed.

The role of transporters in cancer redox homeostasis and cross-talk with nanomedicines

Tumor cell usually exhibits high levels of reactive oxygen species and adaptive antioxidant system due to the metabolic,genetic,and microenvironment-associated alterations.The altered redox homeostasis can promote tumor progression,development,and treatment resistance.Several membrane transporters are involved in the resetting redox homeostasis and play important roles in tumor progression.Therefore,targeting the involved transporters to disrupt the altered redox balance emerges as a viable strategy for cancer therapy.In addition,nanomedicines have drawn much attention in the past decades.Using nanomedicines to target or reset the redox homeostasis alone or combined with other therapies has brought convincing data in cancer treatment.In this review,we will introduce the altered redox balance in cancer metabolism and involved transporters,and highlight the recent advancements of redox-modulating nanomedicines for cancer treatment.

Recent Advances of D-α-tocopherol Polyethylene Glycol 1000 Succinate Based Stimuli-responsive Nanomedicine for Cancer Treatment

D-a-tocopherol polyethylene glycol 1000 succinate(TPGS)is a pharmaceutical excipient approved by Chinese NMPA and FDA of USA.It's widely applied as a multifunctional drug carrier for nanomedicine.The advantages of TPGS include P-glycoprotein(P-gp)inhibition,penetration promotion,apoptosis induction via mitochondrial-associated apoptotic pathways,multidrug resistant(MDR)reversion,metastasis inhibition and so on.TPGS-based drug delivery systems which are responding to extermal stimulus can combine the inhibitory functions of TPGS towards P-gp with the environmentally responsive controlled release property and thus exerts a synergistic anti-cancer effect,through increased intracellular drug concentration in tumors cells and well-controlled drug release behavior.In this review,TPGS-based nano-sized delivery systems responsive to different stimuli were summarized and discussed,including pH-responsive,redox-responsive and multi-responsive systems in various formulations.The achievements,mechanisms and diffcrent characteristics of TPGS-bascd stimuli-responsive drug-delivery systems in tumor therapy were also outlined.

γ⁃Fe2O3@carboxymethyl Cellulose as Potential Oral Nanomedicine for Iron Deficiency Anemia Treatment on Rats

Oral iron supplements such as ferrous iron salts are major treatment agents for iron deficiency anemia(IDA)due to the convenience of large dose administration and good patient compliance.However,the gastrointestinal adverse impact caused by Fe2+stimulus and low bioavailability severely impedes its therapeutic effects.In recent years,it has been found that nano iron⁃based nanoparticles with high surface⁃to⁃volume ratio and low iron ion leakage can alleviate the toxic effect and improve the gastrointestinal absorbance.For further clinical development,nano materials need to meet the pharmaceutical quality demand.Carboxymethyl cellulose(CMC)is a significant pharmaceutical ingredient applied in approved drug formulations,and polyglucosorbitol carboxymethylether(PSC)has been utilized in iron⁃based nanomedicine ferumoxytol synthesis,both of which can be firmly anchored on iron oxide by carboxyl chelation.In this work,iron oxide nanoparticles(NPs)modified with CMC were designed and synthesized,and the structure composition and physicochemical properties were distinctly characterized.Oral supplement effects on rat IDA were investigated and compared with other recently reported iron supplements including NPs modified with PSC.Results show that the oral nano iron supplement achieved the recovery of hemoglobin and serum iron level in only two weeks with high safety.The nano iron oxide modified with pharmaceutical excipients provides new potential approach for oral iron supplement available in clinics.

Nanomedicine strategies for sustained,controlled,and targeted treatment of cancer stem cells of the digestive system

Cancer stem cells(CSCs) constitute a small proportion of the cancer cells that have self-renewal capacity and tumor-initiating ability.They have been identified in a variety of tumors,including tumors of the digestive system.CSCs exhibit some unique characteristics,which are responsible for cancer metastasis and recurrence.Consequently,the development of effective therapeutic strategies against CSCs plays a key role in increasing the efficacy of cancer therapy.Several potential approaches to target CSCs of the digestive system have been explored,including targeting CSC surface markers and signaling pathways,inducing the differentiation of CSCs,altering the tumor microenvironment or niche,and inhibiting ATP-driven efflux transporters.However,conventional therapies may not successfully eradicate CSCs owing to various problems,including poor solubility,stability,rapid clearance,poor cellular uptake,and unacceptable cytotoxicity.Nanomedicine strategies,which include drug,gene,targeted,and combinational delivery,could solve these problems and significantly improve the therapeutic index.This review briefly summarizes the ongoing development of strategies and nanomedicine-based therapies against CSCs of the digestive system.

Mechanotransduction,nanotechnology,and nanomedicine

Mechanotransduction,a conversion of mechanical forces into biochemical signals,is essential for human development and physiology.It is observable at all levels ranging from the whole body,organs,tissues,organelles down to molecules.Dysregulation results in various diseases such as muscular dystrophies,hypertension-induced vascular and cardiac hypertrophy,altered bone repair and cell deaths.Since mechanotransduction occurs at nanoscale,nanosciences and applied nanotechnology are powerful for studying molecular mechanisms and pathways of mechanotransduction.Atomic force microscopy,magnetic and optical tweezers are commonly used for force measurement and manipulation at the single molecular level.Force is also used to control cells,topographically and mechanically by specific types of nano materials for tissue engineering.Mechanotransduction research will become increasingly important as a sub-discipline under nanomedicine.Here we review nanotechnology approaches using force measurements and manipulations at the molecular and cellular levels during mechanotransduction,which has been increasingly play important role in the advancement of nanomedicine.

Nanotechnology and Nanomedicine: A Promising Avenue for Lung Cancer Diagnosis and Therapy

Lung cancer is a leading cause of cancer-related death worldwide,with a very poor overall five-year survival rate.The intrinsic limitations associated with the conventional diagnosis and therapeutic strategies used for lung cancer have motivated the development of nanotechnology and nanomedicine approaches,in order to improve early diagnosis rate and develop more effective and safer therapeutic options for lung cancer.Cancer nanomedicines aim to individualize drug delivery,diagnosis,and therapy by tailoring them to each patient’s unique physiology and pathological features—on both the genomic and proteomic levels—and have attracted widespread attention in this field.Despite the successful application of nanomedicine techniques in lung cancer research,the clinical translation of nanomedicine approaches remains challenging due to the limited understanding of the interactions that occur between nanotechnology and biology,and the challenges posed by the toxicology,pharmacology,immunology,and largescale manufacturing of nanoparticles.In this review,we highlight the progress and opportunities associated with nanomedicine use for lung cancer treatment and discuss the prospects of this field,together with the challenges associated with clinical translation.

Enhanced permeability and retention effect based nanomedicine, a solution for cancer

Tumor-targeting is becoming more and more important for cancer chemotherapy. Though many molecular-target drugs have been developed in the past two decades which shed some light on targeted tumor therapy,clinical results of those molecular-target drugs are not so encouraging especially for solid tumors, problems mostly relating to the heterogeneity and mutations of target molecules in human solid tumors. More general tumor-targeting strategy is thus anticipated. In this regard, the enhanced permeability and retention(EPR) effect which is a unique phenomenon of solid tumors based on the anatomical and pathophysiological nature of tumor blood vessels, is receiving more and more attentions. This EPR effect now served as a standard for tumor-targeted macromolecular anticancer therapy, namely nanomedicine. Many nanoplatforms have been developed as targeted drug delivery systems, including liposome, polymeric micelles, polymer conjugate, nanoparticles. Ample macromolecular drugs are now approved for clinical use or in clinical stage development, all of which by taking advantage of EPR effect, show superior in vivo pharmacokinetics and remarkable tumor selectivity, resulting in improved antitumor effects with less adverse effects. We thus believe EPR-based nanomedicine will be a solution for cancer in the future, whereas further consideration of factors involved in EPR effect and strategies to augment/improve EPR effect are warranted.

Nanomedicine in the application of uveal melanoma

Rapid advances in nanomedicine have significantly changed many aspects of nanoparticle application to the eye including areas of diagnosis, imaging and more importantly drug delivery. The nanoparticle-based drug delivery systems has provided a solution to various drug solubility-related problems in ophthalmology treatment. Nanostructured compounds could be used to achieve local ocular delivery with minimal unwanted systematic side effects produced by taking advantage of the phagocyte system. In addition, the in vivo control release by nanomaterials encapsulated drugs provides prolong exposure of the compound in the body. Furthermore, certain nanoparticles can overcome important body barriers including the blood-retinal barrier as well as the corneal-retinal barrier of the eye for effective delivery of the drug. In summary, the nanotechnology based drug delivery system may serve as an important tool for uveal melanoma treatment.

Nanomedicine:diagnosis to therapy

It can be said that "small technology" becomes a very useful technology and is replacing the classical technology. Nanotechnology is an applied technology relating to management,construction,synthesis of devices in atomic or molecular level that poses the size between 1 and 100 nanometers.In this short article,the author will summarize important advent in nanodiagnosis and nanotherapy then further extrapolate this for the tropical medicine aspect.

Nanomedicine approaches for treatment of hematologic and oncologic malignancies

Cancer is a leading cause of death worldwide.Nowadays,the therapies are inadequate and spur demand for improved technologies.Rapid growth in nanotechnology and novel nanomedicine products represents an opportunity to achieve sophisticated targeting strategies and multi-functionality.Nanomedicine is increasingly used to develop new cancer diagnosis and treatment methods since this technology can modulate the biodistribution and the target site accumulation of chemotherapeutic drugs,thereby reducing their toxicity.Cancer nanotechnology and cancer immunotherapy are two parallel themes that have emerged over the last few decades while searching for a cure for cancer.Immunotherapy is revolutionizing cancer treatment,as it can achieve unprecedented responses in advanced-stage patients,including complete cures and long-term survival.A deeper understanding of the human immune system allows the establishment of combination regimens in which immunotherapy is combined with other treatment modalities(as in the case of the nanodrug Ferumoxytol).Furthermore,the combination of gene therapy approaches with nanotechnology that aims to silence or express cancer-relevant genes via one-time treatment is gradually progressing from bench to bedside.The most common example includes lipidbased nanoparticles that target VEGF-Αand KRAS pathways.This review focuses on nanoparticle-based platforms utilized in recent advances aiming to increase the efficacy of currently available cancer therapies.The insights provided and the evidence obtained in this paper indicate a bright future ahead for immunooncology applications of engineering nanomedicines.