Smart drug delivery systems to overcome drug resistance in cancer immunotherapy

Cancer immunotherapy,a therapeutic approach that inhibits tumors by activating or strengthening anti-tumor immunity,is currently an important clinical strategy for cancer treatment;however,tumors can develop drug resistance to immune surveillance,resulting in poor response rates and low therapeutic efficacy.In addition,changes in genes and signaling pathways in tumor cells prevent susceptibility to immunotherapeutic agents.Furthermore,tumors create an immunosuppressive microenvironment via immunosuppressive cells and secrete molecules that hinder immune cell and immune modulator infiltration or induce immune cell malfunction.To address these challenges,smart drug delivery systems(SDDSs)have been developed to overcome tumor cell resistance to immunomodulators,restore or boost immune cell activity,and magnify immune responses.To combat resistance to small molecules and monoclonal antibodies,SDDSs are used to co-deliver numerous therapeutic agents to tumor cells or immunosuppressive cells,thus increasing the drug concentration at the target site and improving efficacy.Herein,we discuss how SDDSs overcome drug resistance during cancer immunotherapy,with a focus on recent SDDS advances in thwarting drug resistance in immunotherapy by combining immunogenic cell death with immunotherapy and reversing the tumor immunosuppressive microenvironment.SDDSs that modulate the interferon signaling pathway and improve the efficacy of cell therapies are also presented.Finally,we discuss potential future SDDS perspectives in overcoming drug resistance in cancer immunotherapy.We believe that this review will contribute to the rational design of SDDSs and development of novel techniques to overcome immunotherapy resistance.

Smart stimuli-responsive drug delivery systems in spotlight of COVID-19

The world has been dealing with a novel severe acute respiratory syndrome(SARS-CoV-2)since the end of 2019,which threatens the lives of many peopleworldwide.COVID-19 causes respiratory infection with different symptoms,from sneezing and coughing to pneumonia and sometimes gastric symptoms.Researchers worldwide are actively developing novel drug delivery systems(DDSs),such as stimuli-responsive DDSs.The ability of these carriers to respond to external/internal and even multiple stimuli is essential in creating“smart”DDS that can effectively control dosage,sustained release,individual variations,and targeted delivery.To conduct a comprehensive literature survey for this article,the terms“Stimuli-responsive”,“COVID-19”and“Drug delivery”were searched on databases/search engines like“Google Scholar”,“NCBI”,“PubMed”,and“Science Direct”.Many different types of DDSs have been proposed,including those responsive to various exogenous(light,heat,ultrasound andmagnetic field)or endogenous(microenvironmental changes in pH,ROS and enzymes)stimuli.Despite significant progress in DDS research,several challenging issues must be addressed to fill the gaps in the literature.Therefore,this study reviews the drug release mechanisms and applications of endogenous/exogenous stimuli-responsive DDSs while also exploring their potential with respect to COVID-19.

A biomimetic and bioactive scaffold with intelligently pulsatile teriparatide delivery for local and systemic osteoporosis regeneration

Osteoporosis is one of the most disabling consequences of aging,osteoporotic fractures and higher risk of the subsequent fractures leading to substantial disability and deaths,indicating both local fractures healing and the early anti-osteoporosis therapy are of great significance.Teriparatide is strong bone formation promoter effective in treating osteoporosis,while side effects limit clinical applications.Traditional drug delivery is lack of sensitive and short-term release,finding a new non-invasive and easily controllable drug delivery to not only repair the local fractures but also improve total bone mass has remained a great challenge.Thus,bioinspired by the natural bone components,we develop appropriate interactions between inorganic biological scaffolds and organic drug molecules,achieving both loaded with the teriparatide in the scaffold and capable of releasing on demand.Herein,biomimetic bone microstructure of mesoporous bioglass,a near-infrared ray triggered switch,thermosensitive liposomes based on a valve,and polydopamine coated as a heater is developed rationally for osteoporotic bone regeneration.Teriparatide is pulsatile released from intelligent delivery,not only rejuvenating osteoporotic bone defect,but also presenting strong systemic anti-osteoporosis therapy.This biomimetic bone carrying novel drug delivery platform is well worth expecting to be a new promising strategy and clinically commercialized to help patients survive from the osteoporotic fracture.

Recent advances of two-dimensional materials in smart drug delivery nanosystems

Smart drug delivery nano-systems show significant changes in their physical or chemical properties in response to slight change in environmental physical and/or chemical signals,and further releasing drugs adjusted to the progression of the disease at the right target and rate intelligently.Two-dimensional materials possess dramatic status extend all over various scientific and technological disciplines by reason of their exceptional unique properties in application of smart drug delivery nano-systems.In this review,we summarized current progress to highlight various kinds of two-dimensional materials drug carriers which are widely explored in smart drug delivery systems as well as classification of stimuli responsive two-dimensional materials and the advantages and disadvantages of their applications.Consequently,we anticipate that this review might inspire the development of new two-dimensional materials with smart drug delivery systems,and deepen researchers’understanding of smart nano-carries based on two-dimensional materials.

Intelligent polymeric hydrogen sulfide delivery systems for therapeutic applications

Hydrogen sulfide(H_(2)S)plays an important role in regulating various pathological processes such as protecting mammalian cell from harmful injuries,promoting tissue regeneration,and regulating the process of various diseases caused by physiological disorders.Studies have revealed that the physiological effects of H_(2)S are highly associated with its concentrations.At relatively low concentration,H_(2)S shows beneficial functions.However,long-time and high-dose donation of H_(2)S would inhibit regular biological process,resulting in cell dysfunction and apoptosis.To regulate the dosage of H_(2)S delivery for precision medicine,H_(2)S delivery systems with intelligent characteristics were developed and a variety of biocompatibility polymers have been utilized to establish intelligent polymeric H_(2)S delivery systems,with the abilities to specifically target the lesions,smartly respond to pathological microenvironments,as well as real-timely monitor H_(2)S delivery and lesion conditions by incorporating imaging-capable moieties.In this review,we focus on the design,preparation,and therapeutic applications of intelligent polymeric H_(2)S delivery systems in cardiovascular therapy,inflammatory therapy,tissue regenerative therapy,cancer therapy and bacteria-associated therapy.Strategies for precise H_(2)S therapies especially imaging-guided H_(2)S theranostics are highlighted.Since H_(2)S donors with stimuli-responsive characters are vital components for establishing intelligent H_(2)S delivery systems,the development of H_(2)S donors is also briefly introduced.

Environment-responsive drug delivery systems for targeted cancer therapy

In order to deliver and/or release anti-cancer therapeutics at the tumor sites, novel environment-responsive drug delivery systems are designed to specifically respond to tumor microenvironment （such as low pH and hypoxia）. Due to their extraordinary advantages, these environment-responsive drug delivery systems can improve antitumor efficacy, and most importantly, they can decrease toxicity associated with the anti-cancer therapeutics. This review highlights different mechanisms of environmentresponsive drug delivery systems and their applications for targeted cancer therapy.

Temperature and Tumor Microenvironment Dual Responsive Mesoporous Magnetic Nanospheres for Magnetothermal Effect-Induced Cancer Theranostics

The development of smart drug delivery systems(SDDSs)based on engineered nanomaterials is important for clinical applications.Nevertheless,controllable administration of chemotherapeutic drugs for deep tumors and the avoidance of side effects caused by off-targeting during delivery remain a great challenge.Herein,a stimulus-responsive system of mesoporous nanospheres(composed of Cu@Fe_(2)C@mSiO_(2))with good magnetothermal effect is introduced into the tumor microenvironment.This system plays an important role in image-guided controllable targeted drug delivery that is independent of tumor depth.Aggregation-induced emission luminogen-based fluorescence imaging and magnetic resonance imaging were utilized since these techniques visualize the delivery process in real time.In addition,the degraded nanocarriers showed high catalytic activity for Fenton and Fenton-like reactions,upregulating the level of hydroxyl radicals(•OH)in cancer cells to realize chemodynamic therapy.The induced•OH led to the overexpression of pho-STAT3,activating the STAT3 signaling pathway,eventually inducing cancer cell apoptosis.Through metabolic monitoring,this SDDS is removed from the body after its degradation in vivo.The synergistically enhanced therapeutic effect was obtained in the chemo-chemodynamic therapy of 4T1 tumor-bearing mice,offering a platform for efficient cancer therapy with a personalized theranostic strategy.