Sonodynamic therapy (SDT), as an emerging tumor therapeutic modality, has demonstrated tremendous advantages in cancer treatment owing to its minimally invasive nature and robust tissue penetration capability. However, the high concentration of glutathione (GSH) in the tumor microenvironment tends to reduce ROS, which impairs the therapeutic efficacy of SDT. In this study, MBE nanozyme delivery system (where M denotes MnCO3, B represents BPTES, and E stands for exosome membrane) was developed. Leveraging CD63 on the surface of exosome membranes, the MBE can precisely target tumor cells. Subsequently, upon ultrasound (US) irradiation, the MBE nanozyme delivery system releases MnCO3 and BPTES. As an excellent sonosensitizer with favorable biocompatibility, MnCO3 possesses a narrow band gap and peroxidase (POD)-like activity. Under US activation, it can catalyze H2O2 to generate various ROS. such as singlet oxygen(1O2) and hydroxyl radicals(center dot OH). As a glutaminase (GLS) inhibitor, BPTES is capable of blocking GSH biosynthesis at its source by downregulating glutaminase expression, which further enhances the tumor-killing efficacy of ROS. This work integrates GSH synthesis suppression into SDT to augment its anti-tumor activity. This synergistic therapeutic modality enables profound tumor inhibition, paving the way for innovative translational research in tumor treatment.

Messenger RNA (mRNA) vaccine was emerging as a promising treatment for tumor immunotherapy. Highly efficient antigen-presenting ability in tumor immunotherapy through splenic dendritic cell (DC)-targeting mRNA delivery system was very important, but it remained a great challenge. In this study, a library of gemini-like ionizable lipid (termed H-type ionizable lipid, HIL) was synthesized and used for constructing mRNA-encapsulated nanoparticles (mRNA/HNPs) for in vivo mRNA delivery. Structure-activity relationship (SAR) analysis indicated that the spleen-targeting transfection efficiencies of mRNA were strongly correlated with the apparent pKa values of mRNA/HNPs after intravenous injection. After formulation screening, the optimized mRNA/HNPs based on H18 lipid (mRNA/H18NPs) with an average particle size of 124.4 ± 2.4 nm and a multilamellar concentric nanostructure were successfully prepared. Interestingly, without any ligand modification, the mOVA/H18NPs exhibited splenic DC-targeting mRNA transfection, and markedly increased the amounts of IFN-γ+ CD8+ T cells and effector memory CD8+ T cells. Furthermore, in vivo results demonstrated that mRNA/H18NPs encapsulating antigen-encoding mRNA including ovalbumin (OVA) or tyrosinase-related protein 2 (Trp2) effectively activated antigen-specific CD8+ T cells and resulted in significant antitumor efficacy in both B16-OVA or B16F10 tumor-bearing mouse models following intravenous administration. Especially, different from the mOVA/MC3-LNPs group, the mOVA/H18NPs exhibited complete inhibition of tumor progression when it used as preventative cancer vaccines in B16-OVA tumor-bearing mouse model. These findings highlighted that mRNA/H18NPs offer a promising splenic DC-targeting delivery system for mRNA vaccines.

Liver fibrosis is characterized by an excessive deposition of extracellular matrix, especially collagen type I and type III, which were produced by activated hepatic stellate cells (HSCs). In our study, the lipid nanoparticles co-delivering nintedanib (NDNB) and HSP47 siRNA (LNP-siHSP47/NDNB) were developed for inhibiting collagen secretion by siHSP47-mediated downregulation of collagen-specific molecular chaperone (HSP47) and NDNB-mediated inhibition of procollagen production. Surprisingly, a significantly higher gene silencing efficiency on the mRNA level of HSP47 (at least 1.41-fold) was observed in HSCs treated with LNP-siHSP47/NDNB than that treated with LNP-siHSP47. Meanwhile, NDNB-amplified effects of siHSP47 on inhibiting collagen I and collagen III secretion were demonstrated in HSCs after treated with LNP-siHSP47/NDNB compared to LNP-siHSP47 and LNP-siNC/NDNB. Also, LNP-siHSP47/NDNB treatment effectively inhibited TGF-β secretion, thereby suppressing HSC activation, proliferation, and migration. Furthermore, in the bile duct ligation-induced model and the carbon tetrachloride-induced mouse liver fibrosis model, the results revealed that LNP-siHSP47/NDNB treatment effectively ameliorated collagen deposition, HSCs activation, and liver damage, which were near to those in sham and healthy groups. Therefore, the nanomedicine co-delivering siHSP47 and NDNB would provide a potential and promising approach for enhancing liver fibrosis therapy.

To explore a therapeutic approach with dual functions of activating cytotoxic CD8+ T cells and remodeling immunosuppressive tumor-associated macrophages (TAMs), the engineered macrophage-derived nanovesicles (MAC-PNV) were developed in this study. The MAC-PNV were derived from activated DC-like M1 macrophages after reprogramming macrophages by transcription factors PIB (PU.1, IRF8, and BATF3) and further stimulated with antigenic peptide, lipopolysaccharide (LPS), and interferon-γ (IFN-γ). In vitro results demonstrated that the enriched antigen-presenting complexes and co-stimulatory molecules were displayed on the surface of pro-inflammatory cargo-contained MAC-PNV, which enabled significant activation of CD8+ T cells and repolarization of M2 macrophages towards the M1 phenotype. After peritumoral administration, MAC-PNV alone significantly inhibited tumor growth by promoting the activation and intra-tumoral infiltration of CD8+ T cells, and remodeling the immunosuppressive tumor microenvironment (TME) in B16-OVA-bearing mouse models. More importantly, MAC-PNV remarkably enhanced the anti-tumor efficacy of low-dose liposomal doxorubicin (DOX-Lipo, 1 mg/kg), along with reducing its dose-limiting toxicities in B16-F10-bearing mouse models. This study highlights that the MAC-PNV would be a potential and effective immunomodulatory enhancer for providing a promising combination strategy with clinical chemotherapeutics.

Insufficient activation of stimulator of interferon genes (STING) signaling pathway in tumor-associated dendritic cells limits the efficiency of tumor immunotherapy. Herein, the “three-in-one” IAHA-LaP/siPTPN6 NPs containing lanthanum ions (La 3+ ), cGAMP, and PTPN6 siRNA are developed for triple amplification of the STING pathway. In vitro results demonstrate that La 3+ significantly promotes cGAMP-mediated activation of the STING pathway by enhancing the phosphorylation of STING, TBK1, IRF3, and NF- κ B p65. Moreover, the IAHA-LaP/siPTPN6 NPs further significantly enhance the phosphorylation of STING and NF- κ B p65 and augment K63-linked ubiquitination of STING protein via siPTPN6-mediated downregulation of SHP-1 protein. Furthermore, NPs improve the secretion of IFN β (2.4-fold), IL-6 (1.5-fold), and TNF- α (1.4-fold), thereby promoting DCs maturation compared to the mixture of La 3+ and cGAMP. In vivo results show that the IAHA-LaP/siPTPN6 NPs remarkably inhibit primary tumor growth by increasing the percentage of mature DCs in tumor-draining lymph nodes, polarizing M2/M1 phenotype in TME, and promoting the infiltration of CD8 + T cells into tumors. Moreover, these NPs dramatically prevent the growth of distal tumor by inducing systemic anti-tumor immunity and generating a long-term anti-tumor memory for protection against tumor recurrence in mice bearing bilateral B16F10. These IAHA-LaP/siPTPN6 NPs may offer a promising platform for robust anti-tumor immune responses.

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive erosion of the articular cartilage and inflammation. Mesenchymal stem cells' (MSCs) transplantation in OA treatment is emerging, but its clinical application is still limited by the low efficiency in oriented differentiation. In our study, to improve the therapeutic efficiencies of MSCs in OA treatment by carbonic anhydrase IX (CA9) siRNA (siCA9)-based inflammation regulation and Kartogenin (KGN)-based chondrogenic differentiation, the combination strategy of MSCs and the nanomedicine codelivering KGN and siCA9 (AHK-CaP/siCA9 NPs) was used. In vitro results demonstrated that these NPs could improve the inflammatory microenvironment through repolarization of M1 macrophages to the M2 phenotype by downregulating the expression levels of CA9 mRNA. Meanwhile, these NPs could also enhance the chondrogenesis of bone marrow-derived mesenchymal stem cells (BMSCs) by upregulating the pro-chondrogenic TGF-β1, ACAN, and Col2α1 mRNA levels. Moreover, in an advanced OA mouse model, compared with BMSCs alone group, the lower synovitis score and OARSI score were found in the group of BMSCs plus AHK-CaP/siCA9 NPs, suggesting that this combination approach could effectively inhibit synovitis and promote cartilage regeneration in OA progression. Therefore, the synchronization of regulating the inflammatory microenvironment through macrophage reprogramming (CA9 gene silencing) and promoting MSCs oriented differentiation through a chondrogenic agent (KGN) may be a potential strategy to maximize the therapeutic efficiency of MSCs for OA treatment.

Immunosuppressive microenvironments present critical problems in clinical chemotherapy. To regulate the tumor immune microenvironment for enhancing antitumor effect, a combination of immune checkpoint inhibitors (ICIs) with chemotherapeutics has been applied clinically. In this study, miriplatin (MiPt), the lipidic derivative of 5-fluorouracil (Fu-OA), as well as the programmed death ligand 1 (PD-L1) target siRNA (siPD-L1) were integrated into Lip-Pt/Fu@siPD-L1 nanoparticles (NPs) for chemo-immunotherapy. In vitro results showed that Lip-Pt/Fu@siPD-L1 NPs could exhibit effective siRNA gene silencing and promote the phagocytosis of tumor cells by macrophages. Furthermore, in vivo results revealed that Lip-Pt/Fu@siPD-L1 NPs showed significantly higher anti-tumor efficiency than that of the physical mixing of MiPt, 5-fluorouracil, and Lip@siPD-L1 NPs (delivery of siPD-L1 by liposomes). The best anti-tumor efficiency of Lip-Pt/Fu@siPD-L1 NPs resulted from the synergistic immunotherapeutic effects of MiPt and siPD-L1 based on the inhibition of CD47 expression and the downregulation of PD-L1 in tumor cells, which elicited a robust anti-tumor immune response through the activation of macrophage phagocytosis and immune checkpoint inhibition. The Lip-Pt/Fu@siPD-L1 NPs provide a potential strategy for tumor chemo-immunotherapy.

BACKGROUND:Dilated cardiomyopathy (DCM) has a high mortality rate and is the most common indication for heart transplantation. Our study sought to develop a multiparametric nomogram to assess individualized all-cause mortality or heart transplantation (ACM/HTx) risk in DCM patients.METHODS:The present study is a retrospective cohort study. The demographic, clinical, blood test, and cardiac magnetic resonance imaging (CMRI) data of DCM patients in the tertiary center (Fuwai Hospital) were collected. The primary endpoint was ACM/HTx. The least absolute shrinkage and selection operator (LASSO) Cox regression model was applied for variable selection. Multivariable Cox regression was used to develop a nomogram. The concordance index (C-index), area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA) were used to evaluate the performance of the nomogram.RESULTS:A total of 218 patients were included in the present study. They were randomly divided into a training cohort and a validation cohort. The nomogram was established based on eight variables, including mid-wall late gadolinium enhancement, systolic blood pressure, diastolic blood pressure, left ventricular ejection fraction, left ventricular end-diastolic diameter, left ventricular end-diastolic volume index, free triiodothyronine, and N-terminal pro-B type natriuretic peptide. The AUCs regarding 1-year, 3-year, and 5-year ACM/HTx events were 0.859, 0.831, and 0.840 in the training cohort and 0.770, 0.789, and 0.819 in the validation cohort, respectively. The calibration curve and DCA showed good accuracy and clinical utility of the nomogram.CONCLUSIONS:We established and validated a circulating biomarker- and CMRI-based nomogram that could provide a personalized prediction of ACM/HTx for DCM patients, which might help risk stratification and decision-making in clinical practice.

Mitochondrial permeability transition pore (mPTP) opening is a key hallmark of injured type II alveolar epithelial cells (AECIIs) in idiopathic pulmonary fibrosis (IPF). Inhibiting mPTP opening in AECIIs is considered a potential IPF treatment. Herein, a "double braking" strategy on mPTP by cyclosporin A (CsA) derived ionizable lipid with 3D structure (3D-lipid) binding cyclophilin D (CypD) and siRNA downregulating mitochondrial calcium uniporter (MCU) expression is proposed for treating IPF. 3D-lipid and MCU targeting siRNA (siMCU) are co-assembled to form stable 3D-LNP/siMCU nanoparticles (NPs), along with helper lipids. In vitro results demonstrated that these NPs effectively inhibit mPTP opening by 3D-lipid binding with CypD and siRNA downregulating MCU expression, thereby decreasing damage-associated molecular patterns (DAMPs) release and suppressing epithelial-to-mesenchymal transition (EMT) process in bleomycin-induced A549 cells. In vivo results revealed that 3D-LNP/siMCU NPs effectively ameliorated collagen deposition, pro-fibrotic factors secretion, and fibroblast activation in bleomycin-induced pulmonary fibrosis (PF) mouse models. Moreover, compared to the commercial MC3-based formulation, optimized Opt-MC3/siRNA NPs with incorporating 3D-lipid as the fifth component, showed superior therapeutic efficacy against PF due to their enhanced stability and higher gene silencing efficiency. Overall, the nanomedicine containing 3D-lipid and siMCU will be a promising and potential approach for IPF treatment.

CCCTC-binding factor (CTCF) regulates chromatin organization and is upregulated in pancreatic ductal adenocarcinoma (PDAC). We found that CTCF interacts with HNRNPU through a FLG-AS1-dependent mechanism, facilitating the recruitment of EP300 and activation of the m6A reader IGF2BP2. This activation promotes histone lactylation at the promoter region of IGF2BP2 stimulating the proliferation of PDAC cells. IGF2BP2 enhanced the mRNA stability of CSF1 and MYC. Moreover, FLG-AS1 directly interacts with HNRNPU to modulate alternative splicing of CSF1, thus promoting the M2 polarization of tumor associated macrophages (TAMs) in PDAC. The results indicated that CTCF-induced oncogenic modification of histone lactylation, m6A and alternative spilcing as multi-regulation modes of TAMs reprogramming in PDAC and identifies CTCF as a potential therapeutic target for PDAC immunotherapy whose inhibition M2 polarization through the IGF2BP2/CSF1/CSF1R axis. Curaxin combined with gemcitabine treatment has shown promising antitumor efficacy against PDAC.

FOLFOX regimen, composed of folinic acid, 5-fluorouracil (5-FU) and oxaliplatin (OXP), has been used as clinical standard therapeutic regimen in treatments of colorectal cancer (CRC) and esophageal squamous cell carcinoma (ESCC). To further improve its therapeutic outcomes, FOLFOX was combined with anti-PD-1 antibody to form an advanced chemo-immune combination strategy, which has been proven more efficient in controlling cancer progression and prolonging patients' survival in various clinical trials. However, bad tumor accumulation, relative high toxicity, numerous treatment cycles with high fees and low compliance as well as drug resistance seriously limit the prognosis of FOLFOX regimen. The "all-in-one" formulations, which could precisely delivery multidrug regimen into tumor sites and cells, showed a promising application prospect for targeted drug delivery as well as reducing side effects. However, the design and preparation of the "all-in-one" formulation with high drug encapsulation efficiencies for all drugs was still challenging. Herein, a lipid core-shell nanoparticle codelivery platform was designed for simultaneous encapsulation of variant FOLFOX composed of miriplatin (MiPt), 5-Fluoro-2 '-deoxyuridine 5 '-monophosphate (FdUMP), calcium folinate (CF) and PD-L1 siRNA (siPD-L1) with high efficiencies, and their synergistic anti-tumor mechanisms were studied, respectively. MiPt, a precursor of OXP, was validated capable of inducing efficient immunogenic cell death (ICD) in this work. Additionally, ICDmediated release of damage associated molecular patterns functionalized synergistically with PD-L1 silence by siPD-L1 to overcome chemoresistance, reverse suppressive tumor microenvironment and recruit more CD8+ T cells. FdUMP, as the intracellular active form of 5-FU, could induce large amounts of reactive oxygen species to enhance the ICD. CF worked as the sensitizer of FdUMP. The enhanced long-term anti-tumor effect of the prepared "all-in-one" formulation compared to free drug regimen and other controls, was verified in heterotopic CRC mice models and ESCC mice models, providing new thoughts for researchers and showing a promising prospect of translation into clinical applications.

Intrinsic or acquired resistance to chemical drugs severely limits their therapeutic efficacy in cancer treatment. Various intracellular antioxidant molecules, particularly glutathione (GSH), play a crucial role in maintaining intracellular redox homeostasis by mitigating the overproduced reactive oxygen species (ROS) due to rapid cell proliferation. Notably, these antioxidants also eliminate chemical-drug-induced ROS, eventually diminishing their cytotoxicity and rendering them less effective. In this study, we combined erastin, a GSH biosynthesis inhibitor, with 2'-deoxy-5-fluorouridine 5'-monophosphate sodium salt (FdUMP), an ROS-based drug, to effectively disrupt intracellular redox homeostasis and reverse chemotherapy resistance. Therefore, efficient ferroptosis and apoptosis were simultaneously induced for enhanced antitumor effects. Additionally, we employed small interfering RNA targeting PD-L1 (siPD-L1) as a third agent to block immune-checkpoint recognition by CD8+ T cells. The highly immunogenic cell peroxidates or damage-associated molecular patterns (DAMPs) induced by erastin acted synergistically with downregulated PD-L1 to enhance the antitumor effects. To codeliver these three drugs simultaneously and efficiently, we designed GE11 peptide-modified lipid nanoparticles (LNPs) containing calcium phosphate cores to achieve high encapsulation efficiencies. In vitro studies verified its enhanced cytotoxicity, efficient intracellular ROS induction and GSH/GPX4 downregulation, substantial lipid peroxidation product accumulation, and mitochondrial depolarization. In vivo, this formulation effectively accumulated at tumor sites and achieved significant tumor inhibition in subcutaneous colon cancer (CRC) mouse models with a maximum tumor inhibition rate of 83.89% at a relatively low dose. Overall, a strategy to overcome clinical drug resistance was verified in this study by depleting GSH and activating adaptive immunity.

Ferritin is an endogenous protein which is self-assembled by 24 subunits into a highly uniform nanocage structure. Due to the drug-encapsulating ability in the hollow inner cavity and abundant modification sites on the outer surface, ferritin nanocage has been demonstrated great potential to become a multi-functional nanomedicine platform. Its good biocompatibility, low toxicity and immunogenicity, intrinsic tumor-targeting ability, high stability, low cost and massive production, together make ferritin nanocage stand out from other nanocarriers. In this review, we summarized ferritin-based nanomedicine in field of disease diagnosis, treatment and prevention. The different types of drugs to be loaded in ferritin, as well as drug-loading methods were classified. The strategies for site-specific and non-specific functional modification of ferritin were investigated, then the application of ferritin for disease imaging, drug delivery and vaccine development were discussed. Finally, the challenges restricting the clinical translation of ferritin-based nanomedicines were analyzed.

Abstract Background Cardiometabolic disease is a clinical syndrome characterized by multiple metabolic disorders, with atherosclerosis as the core and cardiovascular and cerebrovascular events as the outcome. Drug research and development (R&D) in cardiometabolic diseases has grown rapidly worldwide. However, the development of cardiometabolic drug clinical trials in China remains unclear. This study aims to depict the changing landscape of drug clinical trials for cardiometabolic diseases in China during 2009–2021. Methods The detailed information of drug trials on cardiometabolic diseases registered in the National Medical Products Administration (NMPA) Registration and Information Disclosure Platform was collected between January 1, 2009, and July 1, 2021. The landscape of cardiometabolic drug clinical trials was analyzed by the characteristics, time trends, indications, pharmacological mechanisms, and geographical distribution. Results A total of 2466 drug clinical trials on cardiometabolic diseases were extracted and analyzed. The annual number of drug trials increased rapidly in the past twelve years. Among all the trials, the bioequivalence trials (1428; 58.3%) accounted for the largest proportion, followed by phase I (555; 22.5%), phase III (278; 11.3%), phase II (169; 6.9%), and phase IV (26; 1.1%). Of 2466 trials, 2133 (86.5%) trials were monomer drugs, only 236 (9.6%) trials were polypills and 97 (3.9%) were traditional Chinese medicine (TCM) compounds. In terms of pharmacological mechanisms, the number of trials in dihydropyridine (DHP) calcium antagonists 321 (11.9%) ranked first, while trials in angiotensin receptor blocker (ARB) 289 (10.7%) and dipeptidyl peptidase-4 (DPP-4) inhibitor 205 (7.6%) ranked second and third place respectively. Of 236 chemical polypills trials, 23 (9.7%) polypills were the combination of DHP calcium antagonists and statins, while others were the combination of two same pharmacological effect agents. As for the geographical distribution of leading units, 36 trials were led by principal investigators (PI) units from Beijing, followed by Jiangsu (n = 29), Shanghai (n = 19), Guangdong (n = 19), and Hunan (n = 19), showing an uneven regional distribution. Conclusions Great progress has been made in drug clinical trials on cardiometabolic diseases, especially in antihypertensive agents, hypoglycemic agents, and hypolipidemic agents. However, the insufficient innovation of first-in-class drugs and polypills should be carefully considered by all stakeholders in drug trials.

In clinic,the combination of intravenous pembrolizumab(PD-1 monoclonal antibody)with oral Lenva-tinib(LEN)exhibited an enhanced synergistic benefit for cancer therapy.However,the clinical outcomes were always limited by the problems of inconsistent pharmacokinetic profiles of two drugs,lower drug accumulation in tumor and obvious side effects during the combination therapy.Here,in situ-forming thermosensitive hydrogels based on PLGA-PEG-PLGA triblock copolymers were prepared for local admin-istration of anti-PD1 and LEN(P&L@Gel)to improve therapeutic efficacy and safety.After peritumoral or surgical resection site injection,the significant increased concentrations of both drugs in tumor were observed with the local sustained release of P&L@Gel.In comparison with the group of intraperitoneal anti-PD1 plus oral LEN(P-ip&L-po),significantly higher tumor inhibition efficiency on CT26 tumor mod-els could be obtained in P&L@Gel group,even at the dose of one-eighth of the former,same tumor-inhibition effects could be achieved.The enhanced antitumor efficacy of P&L@Gel group was probably associated with the 2.2 folds of increased level of CD8+T cells and the polarization of tumor associated macrophage from M2 to M1 along with the increased drug accumulation.Moreover,compared with the obvious side effects of P-ip&L-po group,no significant changes of PLT,ALT and UA in blood,as well as IL-1α and IL-1β in mice paws were observed between P&L@Gel group and untreated group.These re-sults suggested that local administration of anti-PD1 and LEN with thermosensitive hydrogel could offer a potential strategy for tumors or tumor postoperative adjuvant treatment.

Osteoarthritis (OA) is a progressive joint disease characterized by inflammation and cartilage destruction, and its progression is closely related to imbalances in the M1/M2 synovial macrophages. A two-pronged strategy for the regulation of intracellular/extracellular nitric oxide (NO) and hydrogen protons for reprogramming M1/M2 synovial macrophages is proposed. The combination of carbonic anhydrase IX (CA9) siRNA and NO scavenger in "two-in-one" nanocarriers (NAHA-CaP/siRNA nanoparticles) is developed for progressive OA therapy by scavenging NO and inhibiting CA9 expression in synovial macrophages. In vitro experiments demonstrate that these NPs can significantly scavenge intracellular NO similar to the levels as those in the normal group and downregulate the expression levels of CA9 mRNA (≈90%), thereby repolarizing the M1 macrophages into the M2 phenotype and increasing the expression levels of pro-chondrogenic TGF-β1 mRNA (≈1.3-fold), and inhibiting chondrocyte apoptosis. Furthermore, in vivo experiments show that the NPs have great anti-inflammation, cartilage protection and repair effects, thereby effectively alleviating OA progression in both monoiodoacetic acid-induced early and late OA mouse models and a surgical destabilization of medial meniscus-induced OA rat model. Therefore, the siCA9 and NO scavenger "two-in-one" delivery system is a potential and efficient strategy for progressive OA treatment.

Antibody–drug conjugates (ADC) utilizing the targeting properties of antibodies and therapeutic effects of drugs have emerged a rapid development in recent years. However, the relatively low drug loading capacity of ADC systems commonly results in failure in delivering enough chemical drugs to the desired areas given a safe antibody dose, therefore the therapeutic efficacy of ADC systems is restricted. With the FDA approval of four siRNA drugs, patisiran, givosiran, lumasiran and inclisiran, the development of siRNAs has regained huge attention of researchers, where the design of delivery system for siRNAs is the key issue for further clinical applications. Inspired by the concept of ADC, the antibody–siRNA conjugates (ARC) have emerged as a potential vehicle for targeted siRNA drug delivery, with the ability to overcome the current obstacles in siRNA delivery. In this review, we summarized the efforts in the development of antibody–siRNA conjugates and hope to provide a basic view for researchers who are interested in this field.

RNA-based therapy is a promising and potential strategy for disease treatment by introducing exogenous nucleic acids such as messenger RNA (mRNA), small interfering RNA (siRNA), microRNA (miRNA) or antisense oligonucleotides (ASO) to modulate gene expression in specific cells. It is exciting that mRNA encoding the spike protein of COVID-19 (coronavirus disease 2019) delivered by lipid nanoparticles (LNPs) exhibits the efficient protection of lungs infection against the virus. In this review, we introduce the biological barriers to RNA delivery in vivo and discuss recent advances in non-viral delivery systems, such as lipid-based nanoparticles, polymeric nanoparticles, N-acetylgalactosamine (GalNAc)-siRNA conjugate, and biomimetic nanovectors, which can protect RNAs against degradation by ribonucleases, accumulate in specific tissue, facilitate cell internalization, and allow for the controlled release of the encapsulated therapeutics.

肿瘤作为全球危害人类健康的重大疾病之一,亟需寻找更加安全高效的治疗方案.核糖核酸(ribonucleic acid,RNA)药物的基因疗法可以调节肿瘤相关基因的表达,已在临床前和临床试验中展示出良好的抗肿瘤治疗潜力.基于肿瘤组织在pH、特异性酶浓度或氧化还原梯度变化等微环境信号特征与正常组织存在差异性,各类微环境响应型纳米载体正在被研究开发用于递送RNA药物,实现对肿瘤组织与细胞的靶向递送,提高RNA药物的抗肿瘤疗效并且降低不良反应.本文综述了肿瘤微环境的病生理特征以及各类肿瘤微环境响应型载体策略,旨在为设计安全高效的RNA药物肿瘤靶向递送系统提供参考.

Nano-drug delivery strategies have been highlighted in cancer treatment, and much effort has been made in the optimization of bioavailability, biocompatibility, pharmacokinetics profiles, and in vivo distributions of anticancer nano-drug delivery systems. However, problems still exist in the delicate balance between improved anticancer efficacy and reduced toxicity to normal tissues, and opportunities arise along with the development of smart stimuli-responsive delivery strategies. By on-demand responsiveness towards exogenous or endogenous stimulus, these smart delivery systems hold promise for advanced tumor-specificity as well as controllable release behavior in a spatial-temporal manner. Meanwhile, the blossom of nanotechnology, material sciences, and biomedical sciences has shed light on the diverse modern drug delivery systems with smart characteristics, versatile functions, and modification possibilities. This review summarizes the current progress in various strategies for smart drug delivery systems against malignancies and introduces the representative endogenous and exogenous stimuli-responsive smart delivery systems. It may provide references for researchers in the fields of drug delivery, biomaterials, and nanotechnology.