From structural design to delivery: mRNA therapeutics for cancer immunotherapy.

mRNA therapeutics have emerged as powerful tools for cancer immunotherapy in accordance with their superiority in expressing all sequence-known proteins in vivo. In particular, with a small dosage of delivered mRNA, antigen-presenting cells (APCs) can synthesize mutant neo-antigens and multi-antigens and present epitopes to T lymphocytes to elicit antitumor effects. In addition, expressing receptors like chimeric antigen receptor (CAR), T-cell receptor (TCR), CD134, and immune-modulating factors including cytokines, interferons, and antibodies in specific cells can enhance immunological response against tumors. With the maturation of in vitro transcription (IVT) technology, large-scale and pure mRNA encoding specific proteins can be synthesized quickly. However, the clinical translation of mRNA-based anticancer strategies is restricted by delivering mRNA into target organs or cells and the inadequate endosomal escape efficiency of mRNA. Recently, there have been some advances in mRNA-based cancer immunotherapy, which can be roughly classified as modifications of the mRNA structure and the development of delivery systems, especially the lipid nanoparticle platforms. In this review, the latest strategies for overcoming the limitations of mRNA-based cancer immunotherapies and the recent advances in delivering mRNA into specific organs and cells are summarized. Challenges and opportunities for clinical applications of mRNA-based cancer immunotherapy are also discussed.

[Retracted] MicroRNA­539 inhibits the proliferation and invasion of bladder cancer cells by regulating IGF­1R.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the Transwell invasion assay data shown in Fig. 2C on p. 4921 were strikingly similar to data that had already been submitted for publication in different form in another article written by different authors at a different research institute. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a  reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 17: 4917­4924, 2018; DOI: 10.3892/mmr.2018.8497].

LncRNA-SERB promotes vasculogenic mimicry (VM) formation and tumor metastasis in renal cell carcinoma.

A growing body of evidence shows that vasculogenic mimicry (VM) is closely related to the invasion and metastasis of many tumor cells. Although the estrogen receptor (ER) can promote initiation and progression of renal cell carcinoma (RCC), how the downstream biomolecules are involved, and the detailed mechanisms of how ER expression is elevated in RCC remain to be further elucidated. Here, we discovered that long noncoding RNA (LncRNA)-SERB is highly expressed in tumor cells of RCC patients. We used multiple RCC cells and an in vivo mouse model for our study, and results indicated that LncRNA-SERB could boost RCC VM formation and cell invasion in vitro and in vivo. Although a previous report showed that ERß can affect the VM formation in RCC, it is unclear which factor could upregulate ERß. This is the first study to show LncRNA-SERB can be the upstream regulator of ERß to control RCC progression. Mechanistically, LncRNA-SERB may increase ERß via binding to the promoter area, and ERß functions through transcriptional regulation of zinc finger E-box binding homeobox 1 (ZEB1) to regulate VM formation. These results suggest that LncRNA-SERB promotes RCC cell VM formation and invasion by upregulating the ERß/ZEB1 axis and that therapeutic targeting of this newly identified pathway may better inhibit RCC progression.

A novel coagulation-related lncRNA predicts the prognosis and immune of clear cell renal cell carcinoma.

Renal cell cancer is associated with the coagulation system. Long non-coding RNA (lncRNA) expression is closely associated with the development of clear cell renal cell carcinoma (ccRCC). The aim of this study was to build a novel lncRNA model to predict the prognosis and immunological state of ccRCC. The transcriptomic data and clinical data of ccRCC were retrieved from TCGA database, subsequently, the lasso regression and lambda spectra were used to filter prognostic lncRNAs. ROC curves and the C-index were used to confirm the predictive effectiveness of this model. We also explored the difference in immune infiltration, immune checkpoints, tumor mutation burden (TMB) and drug sensitivity between the high- and low-risk groups. We created an 8 lncRNA model for predicting the outcome of ccRCC. Multivariate Cox regression analysis showed that age, tumor grade, and risk score are independent prognostic factors for ccRCC patients. ROC curve and C-index revealed the model had a good performance in predicting prognosis of ccRCC. GO and KEGG analysis showed that coagulation related genes were related to immune response. In addition, high risk group had greater TMB level and higher immune checkpoints expression. Sorafenib, Imatinib, Pazopanib, and etoposide had higher half maximal inhibitory concentration (IC50) in the high risk group whereas Sunitinib and Bosutinib had lower IC50. This novel coagulation-related long noncoding RNAs model could predict the prognosis of patients with ccRCC, and coagulation-related lncRNA may be connected to the tumor microenvironment and gene mutation of ccRCC.

[Retracted] KIF22 promotes bladder cancer progression by activating the expression of CDCA3.

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that certain of the colony formation assay data shown in Fig. 3A on p. 7 and the immunohistochemistry data in Fig. 5D were strikingly similar to data that had already appeared in previous publications. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were under consideration for publication, prior to its submission to International Journal of Molecular Medicine, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they accepted the decision to retract this paper. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 48: 211, 2021; DOI: 10.3892/ijmm.2021.5044].

FDC-SP as a diagnostic and prognostic biomarker and modulates immune infiltrates in renal cell carcinoma.

BACKGROUND: Renal cell carcinoma (RCC), one of the top 10 causes of cancer death, is responsible for more than 90% of all cases of primary renal cancer worldwide. Follicular dendritic cell-secreted protein (FDC-SP) specifically binds to activated B cells and regulates the generation of antibodies. It is also thought to promote cancer cell invasion and migration, which could help with tumor metastases. This study aimed to assess the efficacy of FDC-SP in the diagnosis and prognosis of RCC and to investigate the relationship between immune infiltration in RCC and these outcomes. RESULTS: RCC tissues had significantly higher levels of FDC-SP protein and mRNA than normal tissues. The high level of FDC-SP expression was linked to the T stage, histological grade, pathological stage, N stage, M stage, and OS event. Functional enrichment analysis identified the major pathways that were enriched as immune response regulation, complement, and coagulation. Immunological checkpoints and immune cell infiltration were observed to substantially correlate with the levels of FDC-SP expression. FDC-SP expression levels showed the ability to precisely distinguish high-grade or high-stage renal cancer (area under the curve (AUC) = 0.830, 0.722), and RCC patients with higher FDC-SP expression levels had worse prognoses. The AUC values for one-, two-, and five-year survival rates were all greater than 0.600. Moreover, the FDC-SP expression is an independent predictive biomarker of OS in RCC patients. CONCLUSION: FDC-SP may be a prospective therapeutic target in RCC as well as a possible diagnostic and prognostic biomarker associated with immune infiltration.

Acid-Ionizable Iron Nanoadjuvant Augments STING Activation for Personalized Vaccination Immunotherapy of Cancer.

The critical challenge for cancer vaccine-induced T-cell immunity is the sustained activation of antigen cross-presentation in antigen-presenting cells (APCs) with innate immune stimulation. In this study, it is first discovered that the clinically used magnetic contrast agents, iron oxide nanoparticles (IONPs), markedly augment the type-I interferon (IFN-I) production profile of the stimulator of interferon genes (STING) agonist MSA-2 and achieve a 16-fold dosage-sparing effect in the human STING haplotype. Acid-ionizable copolymers are coassembled with IONPs and MSA-2 into iron nanoadjuvants to concentrate STING activation in the draining lymph nodes. The top candidate iron nanoadjuvant (PEIM) efficiently delivers the model antigen ovalbumin (OVA) to CD169+ APCs and facilitates antigen cross-presentation to elicit a 55-fold greater frequency of antigen-specific CD8+ cytotoxic T-lymphocyte response than soluble antigen. PEIM@OVA nanovaccine immunization induces potent and durable antitumor immunity to prevent tumor lung metastasis and eliminate established tumors. Moreover, PEIM nanoadjuvant is applicable to deliver autologous tumor antigen and synergizes with immune checkpoint blockade therapy for prevention of postoperative tumor recurrence and distant metastasis in B16-OVA melanoma and MC38 colorectal tumor models. The acid-ionizable iron nanoadjuvant offers a generalizable and readily translatable strategy to augment STING cascade activation and antigen cross-presentation for personalized cancer vaccination immunotherapy.

Redox Dyshomeostasis with Dual Stimuli-Activatable Dihydroartemisinin Nanoparticles to Potentiate Ferroptotic Therapy of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is highly lethal and resistant to conventional therapies, including chemo-, radio-, and immunotherapy. In this study, it is first determined that a combination of dihydroartemisinin (DHA) and RSL-3 (a glutathione peroxidase 4 (GPX4) inhibitor) markedly induced ferroptosis of PDAC tumor cells. A mechanistic study revealed that DHA can react with iron ions to generate carbon radicals and deplete intracellular glutathione, thereby cumulatively triggering the lipid peroxidation of tumor cells with RSL-3-mediated GPX4 inhibition. A DHA-conjugated amphiphilic copolymer is subsequently synthesized, and intracellular acidity and oxidation dual-responsive DHA nanoparticles are further engineered for the tumor-specific co-delivery of DHA and RSL-3. The resultant nanoparticles (PDBA@RSL-3) efficiently induce ferroptosis of tumor cells in the Panc02 tumor-bearing immune-deficient mouse model, and elicit T-cell-based antitumor immunity in the immune-competent mouse model. The combination of PDBA@RSL-3 nanoparticles and programmed death ligand 1 blockade therapy efficiently inhibits PDAC tumor growth in the immune-competent mouse models. This study may provide novel insights for treatment of PDAC with ferroptosis-based immunotherapy.

Effects of kinesio taping therapy on gait and surface electromyography in stroke patients with hemiplegia.

Background: The application of Kinesio Taping (KT) on the lower extremity of stroke patients can improve the quality of somatosensory information by activating lower extremity muscles involved in postural control. Gait analysis and surface electromyography (SEMG) are valuable in assessing the motor ability of the lower extremities. Objective: This study aimed to investigate the effects of KT therapy on gait and SEMG in stroke patients with hemiplegia. Methods: Twenty-one stroke patients were included in the study. KT was applied to the lower extremities of the hemiplegic side. Quantitative gait parameters were measured by a gait analysis system (IDEEA, by MiniSun, United States) and activation of the lower extremity muscles were evaluated by the SEMG (Trigno™ Wireless Systems, Delsys Inc., United States) before and after taping. Step length, stride length, pulling acceleration, swing power, ground impact, and energy expenditure were used to evaluate when patients walk as usual. SEMG signals were collected from the anterior bilateral tibialis (TA) and the lateral gastrocnemius (LG). The root mean square (RMS) value was used to assess muscle activity. SEMG signals were examined before and after KT treatment in three different locomotor conditions of the patients: walking at a natural speed, walking with a weight of 5 kg, dual-tasking walking (walking + calculation task) while carrying a weight of 5 kg. The calculation task was to ask the patients to calculate the result of subtracting 7 from 100 and continuing to subtract 7 from the resulting numbers. Comparisons between two normally distributed samples (before and after KT treatment) were evaluated using the two-tailed, paired Student's t-test. Results: Stride length (0.89 ± 0.19 vs. 0.96 ± 0.23; p = 0.029), pulling acceleration (0.40 ± 0.21 vs. 1.11 ± 0.74; p = 0.005), and swing power (0.42 ± 0.24 vs. 1.14 ± 0.72; p = 0.004) improved in the hemiplegia side after KT treatment. The RMS value of TA SEMG signals in the limbs on the hemiplegia side decreased after KT treatment during dual-tasking walking carrying a weight of 5 kg (3.65 ± 1.31 vs. 2.93 ± 0.95; p = 0.030). Conclusion: KT treatment is effective in altering gait and SEMG characteristics in stroke patients with hemiplegia.

Self-Cooperative Prodrug Nanovesicles Migrate Immune Evasion to Potentiate Chemoradiotherapy in Head and Neck Cancer.

Chemoradiotherapy is the standard of care for the clinical treatment of locally advanced head and neck cancers. However, the combination of ion radiation with free chemotherapeutics yields unsatisfactory therapeutic output and severe side effects due to the nonspecific biodistribution of the anticancer drugs. Herein, a self-cooperative prodrug nanovesicle is reported for highly tumor-specific chemoradiotherapy. The nanovesicles integrating a prodrug of oxaliplatin (OXA) can passively accumulate at the tumor site and penetrate deep into the tumor mass via matrix metalloproteinase 2-mediated cleavage of the polyethylene glycol corona. The OXA prodrug can be restored inside the tumor cells with endogenous glutathione to trigger immunogenic cell death (ICD) of the tumor cells and sensitize the tumor to ion radiation. The nanovesicles can be further loaded with the JAK inhibitor ruxolitinib to abolish chemoradiotherapy-induced programmed death ligand 1 (PD-L1) upregulation on the surface of the tumor cells, thereby prompting chemoradiotherapy-induced immunotherapy by blocking the interferon gamma-Janus kinase-signal transducer and activator of transcription axis. The prodrug nanoplatform reported herein might present a novel strategy to cooperatively enhance chemoradiotherapy of head and cancer and overcome PD-L1-dependent immune evasion.

Dual-targeting prodrug nanotheranostics for NIR-â ¡ fluorescence imaging-guided photo-immunotherapy of glioblastoma.

Glioblastoma (GBM) therapy is severely impaired by the blood-brain barrier (BBB) and invasive tumor growth in the central nervous system. To improve GBM therapy, we herein presented a dual-targeting nanotheranostic for second near-infrared (NIR-II) fluorescence imaging-guided photo-immunotherapy. Firstly, a NIR-Ⅱ fluorophore MRP bearing donor-acceptor-donor (D-A-D) backbone was synthesized. Then, the prodrug nanotheranostics were prepared by self-assembling MRP with a prodrug of JQ1 (JPC) and T7 ligand-modified PEG5k-DSPE. T7 can cross the BBB for tumor-targeted delivery of JPC and MRP. JQ1 could be restored from JPC at the tumor site for suppressing interferon gamma-inducible programmed death ligand 1 expression in the tumor cells. MRP could generate NIR-II fluorescence to navigate 808 nm laser, induce a photothermal effect to trigger in-situ antigen release at the tumor site, and ultimately elicit antitumor immunogenicity. Photo-immunotherapy with JPC and MRP dual-loaded nanoparticles remarkably inhibited GBM tumor growth in vivo. The dual-targeting nanotheranostic might represent a novel nanoplatform for precise photo-immunotherapy of GBM.

Sequentially Activatable Polypeptide Nanoparticles for Combinatory Photodynamic Chemotherapy of Breast Cancer.

Stimuli-activatable nanomaterials hold significant promise for tumor-specific drug delivery by recognizing the internal or external stimulus. Herein, we reported a dual-responsive and biodegradable polypeptide nanoparticle (PPTP@PTX2 NP) for combinatory chemotherapy and photodynamic therapy (PDT) of breast cancer. The NPs were engineered by encapsulating diselenide bond linked dimeric prodrug of paclitaxel (PTX2) in an intracellular acidity-activatable polypeptide micelle. Specifically, the acid-responsive polypeptide was synthesized by grafting a tetraphenyl porphyrin (TPP) photosensitizer and N,N-diisopropylethylenediamine (DPA) onto the poly(ethylene glycol)-block-poly(glutamic acid) diblock copolymer by the amidation reaction, which self-assembled into micellar NPs and was activated inside the acidic endocytic vesicles to perform PDT. The paclitaxel dimer can be stably loaded into the polypeptide NPs and be restored by PDT inside the tumor cells. The formed PPTP@PTX2 NPs remained inert during blood circulation and passively accumulated in the tumor foci, which could be activated within the endocytic vesicles via acid-triggered protonation of DPA groups to generate fluorescence signal and release PTX2 in 4T1 murine breast tumor cells. Upon 660 nm laser irradiation, the activated NPs carried out PDT via TPP and chemotherapy via PTX to induce apoptosis of 4T1 cells and thereby efficiently inhibited 4T1 tumor growth and prevented metastasis of tumor cells.

Bispecific prodrug nanoparticles circumventing multiple immune resistance mechanisms for promoting cancer immunotherapy.

Cancer immunotherapy is impaired by the intrinsic and adaptive immune resistance. Herein, a bispecific prodrug nanoparticle was engineered for circumventing immune evasion of the tumor cells by targeting multiple immune resistance mechanisms. A disulfide bond-linked bispecific prodrug of NLG919 and JQ1 (namely NJ) was synthesized and self-assembled into a prodrug nanoparticle, which was subsequently coated with a photosensitizer-modified and tumor acidity-activatable diblock copolymer PHP for tumor-specific delivery of NJ. Upon tumor accumulation via passive tumor targeting, the polymeric shell was detached for facilitating intracellular uptake of the bispecific prodrug. NJ was then activated inside the tumor cells for releasing JQ1 and NLG919 via glutathione-mediated cleavage of the disulfide bond. JQ1 is a bromodomain-containing protein 4 inhibitor for abolishing interferon gamma-triggered expression of programmed death ligand 1. In contrast, NLG919 suppresses indoleamine-2,3-dioxygenase 1-mediated tryptophan consumption in the tumor microenvironment, which thus restores robust antitumor immune responses. Photodynamic therapy (PDT) was performed to elicit antitumor immunogenicity by triggering immunogenic cell death of the tumor cells. The combination of PDT and the bispecific prodrug nanoparticle might represent a novel strategy for blockading multiple immune evasion pathways and improving cancer immunotherapy.

Engineered nanomedicines block the PD-1/PD-L1 axis for potentiated cancer immunotherapy.

Immunotherapy, in particular immune checkpoint blockade (ICB) therapy targeting the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis, has remarkably revolutionized cancer treatment in the clinic. Anti-PD-1/PD-L1 therapy is designed to restore the antitumor response of cytotoxic T cells (CTLs) by blocking the interaction between PD-L1 on tumour cells and PD-1 on CTLs. Nevertheless, current anti-PD-1/PD-L1 therapy suffers from poor therapeutic outcomes in a large variety of solid tumours due to insufficient tumour specificity, severe cytotoxic effects, and the occurrence of immune resistance. In recent years, nanosized drug delivery systems (NDDSs), endowed with highly efficient tumour targeting and versatility for combination therapy, have paved a new avenue for cancer immunotherapy. In this review article, we summarized the recent advances in NDDSs for anti-PD-1/PD-L1 therapy. We then discussed the challenges and further provided perspectives to promote the clinical application of NDDS-based anti-PD-1/PD-L1 therapy.

A Copper-Based Biosensor for Dual-Mode Glucose Detection.

Glucose is a source of energy for daily activities of the human body and is regarded as a clinical biomarker, due to the abnormal glucose level in the blood leading to many endocrine metabolic diseases. Thus, it is indispensable to develop simple, accurate, and sensitive methods for glucose detection. However, the current methods mainly depend on natural enzymes, which are unstable, hard to prepare, and expensive, limiting the extensive applications in clinics. Herein, we propose a dual-mode Cu2O nanoparticles (NPs) based biosensor for glucose analysis based on colorimetric assay and laser desorption/ionization mass spectrometry (LDI MS). Cu2O NPs exhibited excellent peroxidase-like activity and served as a matrix for LDI MS analysis, achieving visual and accurate quantitative analysis of glucose in serum. Our proposed method possesses promising application values in clinical disease diagnostics and monitoring.

KIF22 promotes bladder cancer progression by activating the expression of CDCA3.

Bladder cancer is a common malignant tumor of the urinary system and is associated with a high morbidity and mortality, due to the difficulty in the accurate diagnosis of patients with early­stage bladder cancer and the lack of effective treatments for patients with advanced bladder cancer. Thus, novel therapeutic targets are urgently required for this disease. Kinesin family member 22 (KIF22) is a kinesin­like DNA binding protein belonging to kinesin family, and is involved in the regulation of mitosis. KIF22 has also been reported to promote the progression of several types of cancer, such as breast cancer and melanoma. The present study demonstrates the high expression of KIF22 in human bladder cancer tissues. KIF22 was found to be associated with clinical features, including clinical stage (P=0.003) and recurrence (P=0.016), and to be associated with the prognosis of patients with bladder cancer. Furthermore, it was found that KIF22 silencing inhibited the proliferation of bladder cancer cells in vitro and tumor progression in mice. Additionally, it was noted that KIF22 transcriptionally activated cell division cycle­associated protein 3 expression, which was also confirmed in tumors in mice. Taken together, the present study investigated the molecular mechanisms underlying the promotion of bladder cancer by KIF22 and provide a novel therapeutic target for the treatment of bladder cancer. Introduction.

Effect of EGCG on bronchial epithelial cell premalignant lesions induced by cigarette smoke and on its CYP1A1 expression.

Epigallocatechin­3­gallate (EGCG) has been demonstrated to exhibit anticancer effects; however, the mechanisms behind these are not yet clear. The objective of the present study was to assess the effect of EGCG on smoking­induced, precancerous, bronchial epithelial cell lesions and determine a potential protective mechanism. Human bronchial epithelial (HBE) cells were treated with cigarette smoke extract (CSE). Benzopyrene­DNA adducts were detected by immunofluorescence cytochemistry. Changes to microRNA (miRNA) expression levels were detected via microarray. The effects of EGCG on smoke­induced benzopyrene­DNA adduct formation and the subsequent change in miRNA expression were analyzed. Subsequently, the protective effect of EGCG on smoke inhalation­induced precancerous lesions was investigated. The expression levels of miRNA target genes were also analyzed. After CSE treatment, benzopyrene­DNA adducts appeared in HBE cells, along with a resultant change in miRNA expression. EGCG inhibited the effects of CSE exposure; benzopyrene­DNA adduct formation was reduced and miRNA expression changes were suppressed. In vivo, EGCG significantly reduced benzopyrene­DNA adduct formation and the subsequent development of precancerous lesions in rat lungs induced by cigarette smoke inhalation. Moreover, EGCG downregulated CYP1A1 overexpression, a target gene of multiple smoking­induced miRNAs, in rat lungs. EGCG may reduce the risk of lung cancer by downregulating the expression of the key gene CYP1A1, preventing the formation of smoking­induced benzopyrene­DNA adducts and alleviating smoking­induced bronchial epithelial dysplasia and heterogeneity.

Stimuli-Sheddable Nanomedicine Overcoming Pathophysiological Barriers for Potentiating Immunotherapy of Cancer.

Immunotherapy displays potent potential for clinical cancer management by activating the protective immune response; however, the microenvironment of the immunosuppressive tumor restricts the efficiency of immunotherapies. Along with the complex pathophysiological barrier of the solid tumors, successful immunotherapeutic delivery remains a formidable challenge for conventional nanomedicine. Stimuli-sheddable nano vectors may facilitate the delivery of cargoes to tumors with minimal premature cargo leakage in blood circulation while enhancing the tumor penetration of nanomedicines by deshielding the polyethylene glycol (PEG) corona upon endogenous activity such as acidity, enzymes and glutathione, or external stimuli, such as laser irradiation. Throughout this study, researchers overviewed the recent advances of nanomedicine-based cancer immunotherapy using the stimuli-responsive deshielding nano vectors, which allowed researchers to integrate multiple therapeutic regimens for inducing immunogenic cell death. This aided in blocking the immune checkpoints, repolarizing the macrophages, and regulating the kynurenine metabolism. Furthermore, researchers discussed the critical issues in the development of stimuli-sheddable nanoimmunodulators, primarily aimed at speeding up their clinical translation. Finally, researchers provided novel perspectives for improving cancer management with the stimuli-sheddable nanomedicine.

Engineering Nanorobots for Tumor-Targeting Drug Delivery: From Dynamic Control to Stimuli-Responsive Strategy.

Nanotechnology has been widely applied to the fabrication of drug delivery systems in the past decades. Recently, with the progress made in microfabrication approaches, nanorobots are steadily becoming a promising means for tumor-targeting drug delivery. In general, nanorobots can be divided into two categories: nanomotors and stimuli-responsive nanorobots. Nanomotors are nanoscale systems with the ability to convert surrounding energies into mechanical motion, whereas stimuli-responsive nanorobots are featured with activatable capacity in response to various endogenous and exogenous stimulations. In this minireview, the dynamic control of nanomotors and the rational design of stimuli-responsive nanorobots are overviewed, with particular emphasis on their contribution to tumor-targeting therapy. Moreover, challenges and perspectives associated with the future development of nanorobots are presented.