Construction of Switch Modules for CAR-T Cell Treatment Using a Site-Specific Conjugation System.

Chimeric antigen receptor T-cell (CAR-T cell) therapy has become a promising treatment option for B-cell hematological tumors. However, few optional target antigens and disease relapse due to loss of target antigens limit the broad clinical applicability of CAR-T cells. Here, we conjugated an antibody (Ab) fusion protein, consisting of an Ab domain and a SpyCatcher domain, with the FITC-SpyTag (FITC-ST) peptide to form a bispecific safety switch module using a site-specific conjugation system. We applied the safety switch module to target CD19, PDL1, or Her2-expressing tumor cells by constructing FMC63 (anti-CD19), antiPDL1, or ZHER (anti-Her2)-FITC-ST, respectively. Those switch modules significantly improved the cytotoxic effects of anti-FITC CAR-T cells on tumor cells. Additionally, we obtained the purified CD8+ T cells by optimizing a shorter version of the CD8-binding aptamer to generate anti-FITC CD8-CAR-T cells, which combined with the CD4-FITC-ST switch module (anti-CD4) to eliminate the CD4-positive tumor cells in vitro and in vivo. Overall, we established a novel safety switch module by site-specific conjugation to enhance the antitumor function of universal CAR-T cells, thereby expanding the application scope of CAR-T therapy and improving its safety and efficacy.

Interpreting and modelling the daily extreme sediment events in karst mountain watersheds.

Increasingly frequent extreme rainfall as a result of climate change is strongly damaging the global soil and water environment. However, few studies have focused on daily extreme sediment events (DESE) in heterogeneous karst watersheds based on long-term in-situ observations. This study quantitatively assessed the time effect of DESE on rainfall response, decoupled the impact of environmental factors on DESE by using structural equation modelling, and finally explored the modelling scheme of DESE based on the hybrid model. The results showed that DESE had the highest frequency of occurrence in May-July, with dispersed distribution in the value domain. Rainfall with a time lag of 1 day and a time accumulation of 2 or 3 days was an important contribution to DESE (P < 0.01, R = 0.47-0.68). Combined effects of environmental factors explained 53.6 %-64.1 % of the variation in DESE. Runoff and vegetation exerted the strongest direct and indirect effects on DESE, respectively (ß = 0.66/-0.727). Vegetation was the dominant driver of DESE in Dabanghe and Yejihe (ß = -0.725/-0.758), while the dominant driver in Tongzhihe was climate (ß = 0.743). In the future, the risk of extreme sediments should be prevented and resolved through the comprehensive regulation of multiple paths, such as runoff and vegetation. Hybrid models significantly improved the modelling performance of machine learning models. Generalized additive model-Extreme gradient boost had the best performance, while Partial least squares regression-Extreme gradient boost was the most valuable when considering performance and input data cost. Two methods can be used as recommended solutions for DESE modelling. This study provides new and in-depth insights into DESE in karst watersheds and helps the region develop forward-looking soil and water management models to cope with future extreme erosion hazards.

The research status and prospects of nanomaterials in wound healing: A scientometric study.

Nanotechnology and nanomaterials have swiftly influenced wound healing, propelling the development of wound-healing nanomaterials. Therefore, it's crucial to gather essential information about prominent researches in this domain. Moreover, identifying primary directions and related frontiers in wound healing and nanomaterials is paramount. This will enhance our comprehension of the current research landscape and foster progress in this field. Retrieved from the Web of Science core database, a total of 838 relevant studies published from 2013 to 2022 were analyzed through bibliometric visualization tools such as CiteSpace, VOSviewer, and Bibliometrics Online Analysis Platform. The annual study count has been rising steadily, primary contributors to this field include China, India, and the United States. The author with the highest output is Zangeneh, Akram, while Grumezescu, Alexandru Mihai garners the most citations. Chinese Academy of Sciences emerges as the leading institution, with Nanomaterials as the predominant journal. The keyword "antibacterial" signals prevailing and forthcoming trends in this domain. This study presents the first scientometric study and bibliometric visualization for wound healing-related nanomaterials, shedding light on research hotspots and trends. Over the course of the decade from 2013 to 2022, enthusiasm for nanomaterials in wound healing research has surged, auguring well for upcoming investigations.

Mission-oriented determination of regional weapon maintenance demand in simulation.

Determining maintenance demand ahead of mission is crucial to practical weapon maintenance, particularly to regional warship weapon maintenance. Attention is paid only to reliability, and the nature of mission or the consequence of damage is ignored while determining the regional warship weapon maintenance demand. For this reason, a method for determining regional maintenance demand based on simulation is put forward in this paper. Regional weapon maintenance system is first analyzed to build a mission-oriented maintenance demand model with the concept of mission-induced failure. Subsequently, the Anylogic platform is employed because of its advantages including agent modeling simulation and visualized process display. Four types of agent are designed for the regional maintenance system. The process of determining maintenance demand based on simulation is established on this basis. An example is eventually taken to calculate and verify the universality and effectiveness of the simulation model.

Microgel-based carriers enhance skeletal stem cell reprogramming towards immunomodulatory phenotype in osteoarthritic therapy.

Skeletal stem cells (SSC) have gained attentions as candidates for the treatment of osteoarthritis due to their osteochondrogenic capacity. However, the immunomodulatory properties of SSC, especially under delivery operations, have been largely ignored. In the study, we found that Pdpn+ and Grem1+ SSC subpopulations owned immunoregulatory potential, and the single-cell RNA sequencing (scRNA-seq) data suggested that the mechanical activation of microgel carriers on SSC induced the generation of Pdpn+Grem1+Ptgs2+ SSC subpopulation, which was potent at suppressing macrophage inflammation. The microgel carriers promoted the YAP nuclear translocation, and the activated YAP protein was necessary for the increased expression of Ptgs2 and PGE2 in microgels-delivered SSC, which further suppressed the expression of TNF-ɑ, IL-1ß and promoted the expression of IL-10 in macrophages. SSC delivered with microgels yielded better preventive effects on articular lesions and macrophage activation in osteoarthritic rats than SSC without microgels. Chemically blocking the YAP and Ptgs2 in microgels-delivered SSC partially abolished the enhanced protection on articular tissues and suppression on osteoarthritic macrophages. Moreover, microgel carriers significantly prolonged SSC retention time in vivo without increasing SSC implanting into osteoarthritic joints. Together, our study demonstrated that microgel carriers enhanced SSC reprogramming towards immunomodulatory phenotype to regulate macrophage phenotype transformation for effectively osteoarthritic therapy by promoting YAP protein translocation into nucleus. The study not only complement and perfect the immunological mechanisms of SSC-based therapy at the single-cell level, but also provide new insight for microgel carriers in stem cell-based therapy.

Rapid discrimination of urine specific gravity using spectroscopy and a modified combination method based on SPA and spectral index.

To achieve high-accuracy urine specific gravity discrimination and guide the design of four-waveband multispectral sensors. A modified combination strategy was attempted to be proposed based on the successive projections algorithm (SPA) and the spectral index (SI) in the present study. First, the SPA was used to select four spectral variables in the full spectra. Second, the four spectral variables were mathematically transformed by SI to obtain SI values. Then, SPA gradually fusions the SI values and establishes models to identify USG. The results showed that the SPA can screen out the four characteristic wavelengths related to the measured sample attributes. SIs can be used to improve the performance of constructed prediction models. The best model only involves four spectral variables and 1 SI value, with high accuracy (91.62%), sensitivity (0.9051), and specificity (0.9667). The results reveal that m-SPA-SI can effectively distinguish USG and provide design guidance for 4-wavelength multispectral sensors.

Omega-3 polyunsaturated fatty acids and its metabolite 12-HEPE rescue busulfan disrupted spermatogenesis via target to GPR120.

Busulfan is an antineoplastic, which is always accompanied with the abnormal of spermatogonia self-renewal and differentiation. It has been demonstrated that the omega-3 polyunsaturated fatty acids (PUFAs) benefits mature spermatozoa. However, whether omega-3 can protect endogenous spermatogonia and the detailed mechanisms are still unclear. Evaluate of spermatogenesis function (in vivo) were examined by histopathological analysis, immunofluorescence staining, and western blotting. The levels of lipid metabolites in testicular tissue were determined via liquid chromatography. We investigated the effect of lipid metabolites on Sertoli cells provided paracrine factors to regulate spermatogonia proliferation and differentiation using co-culture system. In our study, we showed that omega-3 PUFAs significantly improved the process of sperm production and elevated the quantity of both undifferentiated Lin28+ spermatogonia and differentiated c-kit+ spermatogonia in a mouse model where spermatogenic function was disrupted by busulfan. Mass spectrometry revealed an increase in the levels of several omega-3 metabolites in the testes of mice fed with omega-3 PUFAs. The eicosapentaenoic acid metabolite 12-hydroxyeicosapentaenoic acid (12-HEPE) up-regulated bone morphogenic protein 4 (BMP4) expression through GPR120-ERK1/2 pathway activation in Sertoli cells and restored spermatogonia proliferation and differentiation. Our study provides evidence that omega-3 PUFAs metabolite 12-HEPE effectively protects spermatogonia and reveals that GPR120 might be a tractable pharmacological target for fertility in men received chemotherapy or severe spermatogenesis dysfunction.

Erratum: CXCL12-mediated monocyte transmigration into brain perivascular space leads to neuroinflammation and memory deficit in neuropathic pain: Erratum.

[This corrects the article DOI: 10.7150/thno.44364.].

Ecology of End-of-life Medical Care for Advanced Cancer Patients in China.

AIMS: Cancer is a leading cause of death worldwide. Approximately 30% of global cancer-related deaths occur in mainland China. However, there is a paucity of information regarding the end-of-life care-seeking behavior of patients with advanced cancer in China. Our study was to investigate end-of-life care-seeking behavior and to quantify the association between sociodemographic characteristics and the location and pattern of end-of-life care. METHODS: We conducted a mortality follow-back survey using caregivers' interviews to estimate the number of individuals pre 1000 who died between 2013 and 2021 in the last 3 months of life. We collected data on hospitalization, outpatient visits, cardiopulmonary resuscitation, palliative care and hospice utilization, and place of death, stratified by age, gender, marital status, household income, residential zone, insurance type, and the primary end-of-life decision-maker of the decedents. RESULTS: We analyzed data from 857 deceased cancer patients, representing an average of 1000 individuals. Among these patients, 861 experienced at least moderate or more severe pain, 774 were hospitalized at least once, 468 received intensive treatment, 389 had at least one outpatient visit, 270 died in the hospital, 236 received cardiopulmonary resuscitation and 99 received specialist hospice care. CONCLUSIONS: Our study provides insights into the end-of-life care-seeking behavior of advanced cancer patients in China and our findings serve as a useful benchmark for estimating the use of end-of-life medical care. It highlights the need for the establishment of an accessible and patient-centered palliative care and hospice system.

Update on Radiotherapy Changes of Nasopharyngeal Carcinoma Tumor Microenvironment.

The utilization of radiotherapy (RT) serves as the principal approach for managing nasopharyngeal carcinoma (NPC). Consequently, it is imperative to investigate the correlation between the radiation microenvironment and radiation resistance in NPC. PubMed and China National Knowledge Infrastructure (CNKI) databases were accessed to perform a search utilizing the English keywords "nasopharyngeal cancer", "radiotherapy", and "microenvironment". The search time spanned from the establishment of the database until January 20, 2023. A total of 82 articles were included. The post-radiation tumor microenvironment (TME), or the radiation microenvironment, includes several components, such as the radiation-immune microenvironment and the radiation-hypoxic microenvironment. The radiation-immune microenvironment includes various factors like immune cells, signaling molecules, and extracellular matrix. RT can reshape the TME, leading to immune responses with both cytotoxic effects (T cells, B cells, natural killer (NK) cells) and immune escape mechanisms (regulatory T cells (Tregs), macrophages). RT enhances immune responses through DNA release, type I interferons, and immune cell recruitment. Radiation-hypoxic microenvironment affects metabolism and molecular changes. RT-induced hypoxia causes vascular changes, fibrosis, and vessel compression, leading to tissue hypoxia. Hypoxia activates hypoxia-inducible factor (HIF)-1α/2α, promoting angiogenesis and glycolysis in tumor cells. TME changes due to hypoxia also involve immune suppressive cells like myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and Tregs. The radiation microenvironment is involved in radiation resistance and holds a significant effect on the prognosis of patients with NPC. Exploring the radiation microenvironment provides new insights into RT and NPC research.

[A study on the application of cross-frequency coupling characteristics of neural oscillation in the diagnosis of mild cognitive impairment].

In order to fully explore the neural oscillatory coupling characteristics of patients with mild cognitive impairment (MCI), this paper analyzed and compared the strength of the coupling characteristics for 28 MCI patients and 21 normal subjects under six different-frequency combinations. The results showed that the difference in the global phase synchronization index of cross-frequency coupling under δ-θ rhythm combination was statistically significant in the MCI group compared with the normal control group ( P = 0.025, d = 0.398). To further validate this coupling feature, this paper proposed an optimized convolutional neural network model that incorporated a time-frequency data enhancement module and batch normalization layers to prevent overfitting while enhancing the robustness of the model. Based on this optimized model, with the phase locking value matrix of δ-θ rhythm combination as the single input feature, the diagnostic accuracy of MCI patients was (95.49 ± 4.15)%, sensitivity and specificity were (93.71 ± 7.21)% and (97.50 ± 5.34)%, respectively. The results showed that the characteristics of the phase locking value matrix under the combination of δ-θ rhythms can adequately reflect the cognitive status of MCI patients, which is helpful to assist the diagnosis of MCI.

Controllable Si-C Bond Formation from Trihydrosilanes En Route to Synthesis of 1,4-Azasilinanes with Diverse Silyl Functionalities.

A B(C6F5)3-catalyzed controllable inter/intra-/intermolecular Si-C bond formation process has been developed from trihydrosilane and dienamide with alkenes, anilines, or aryl iodides. A variety of 1,4-azasilinanes have been generated with diverse exo-cyclic heteroleptic disubstitutions on silicon, thereby expanding the range of silaazacyclic rings available for the discovery of silicon-containing drugs.

ZDHHC17 participates in the pathogenesis of polycystic ovary syndrome by affecting androgen conversion to estrogen in granulosa cells.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting women of reproductive age and is a significant cause of female subfertility. Our previous research demonstrated that the abnormal palmitoylation of heat shock protein-90α (HSP90α) plays a role in the development of PCOS. However, the palmitoyl acyltransferases in HSP90α palmitoylation remain poorly understood. Herein, we identified ZDHHC17 as a major palmitoyl acyltransferase for HSP90α palmitoylation in granulosa cells. ZDHHC17 protein expression was diminished under excess androgen conditions in vitro and in vivo. Consistently, ovarian ZDHHC17 expression was found to be attenuated in patients with PCOS. ZDHHC17 depletion decreased HSP90α palmitoylation levels and hampered the conversion of androgen to estrogen via CYP19A1. Furthermore, ZDHHC17-mediated regulation of CYP19A1 expression was dependent on HSP90α palmitoylation. Our findings reveal that the regulatory role of HSP90α palmitoylation by ZDHHC17 is critical in PCOS pathophysiology and provide insights into the role of ZDHHC17 in reproductive endocrinology.

Experimental and Numerical Study of Al2219 Powders Deposition on Al2219-T6 Substrate by Cold Spray: Effects of Spray Angle, Traverse Speed, and Standoff Distance.

Cold spray (CS) is an emerging technology for repairing and 3D additive manufacturing of a variety of metallic components using deformable metal powders. In CS deposition, gas type, gas pressure, gas temperature, and powder feed rate are the four key process parameters that have been intensively studied. Spray angle, spray gun traverse speed, and standoff distance (SoD) are the other three process parameters that have been less investigated but are also important, especially when depositing on uneven substrates or building up 3D freeform structures. Herein, the effects of spray angle, traverse speed, and SoD during CS deposition have been investigated holistically on a single material system (i.e., Al2219 powders on Al2219-T6 substrate). The coatings' mass gain, thickness, porosity, and residual stress have been characterized, and the results show that spray angle and traverse speed exercise much more effects than SoD in determining coatings' buildup. Finite element method (FEM) modeling and computational fluid dynamic (CFD) simulation have been carried out to understand the effects of these three parameters for implementing CS as repairing and additive manufacturing using aluminum-based alloy powders.

Maternal RNA binding protein with multiple splicing 2 (RBPMS2) is involved in mouse blastocyst formation through the bone morphogenetic protein pathway.

RESEARCH QUESTION: Is early embryo development in mice influenced by RNA binding protein with multiple splicing 2 (RBPMS2), a maternal factor that accumulates and is stored in the cytoplasm of mature oocytes? DESIGN: The expression patterns of RBPMS2 in mouse were analysed using quantitative real-time PCR (qRT PCR) and immunofluorescence staining. The effect of knockdown of RBPMS2 on embryo development was evaluated through a microinjection of specific morpholino or small interfering RNA. RNA sequencing was performed for mechanistic analysis. The interaction between RBPMS2 and the bone morphogenetic protein (BMP) pathway was studied using BMP inhibitor and activator. The effect on the localization of E-cadherin was determined by immunofluorescence staining. RESULTS: Maternal protein RBPMS2 is highly expressed in mouse oocytes, and knockdown of RBPMS2 inhibits embryo development from the morula to the blastocyst stage. Mechanistically, RNA sequencing showed that the differentially expressed genes were enriched in the transforming growth factor-ß (TGF-ß) signalling pathway. BMPs are members of the TGF-ß superfamily of growth factors. It was found that the addition of BMP inhibitor to the culture medium led to a morula-stage arrest, similar to that seen in RBPMS2 knockdown embryos. This morula-stage arrest defect caused by RBPMS2 knockdown was partially rescued by BMP activator. Furthermore, the localization of E-cadherin to the membrane was impaired in response to a knockdown of RBPMS2 or inhibition of the BMP pathway. CONCLUSION: This study suggests that RBPMS2 activates the BMP pathway and thus influences the localization of E-cadherin, which is important for early mouse embryo development during blastocyst formation.

Enhanced Fluorescence Characteristics of SrAl2O4: Eu2+, Dy3+ Phosphor by Co-Doping Gd3+ and Anti-Counterfeiting Application.

A series of long-afterglow luminescent materials (SrAl2O4: Eu2+ (SAOE), SrAl2O4: Eu2+, Dy3+ (SAOED) and SrAl2O4: Eu2+, Dy3+, Gd3+ (SAOEDG)) was synthesized via the combustion method. Temperature and concentration control experiments were conducted on these materials to determine the optimal reaction temperature and ion doping concentration for each sample. The crystal structure and luminescent properties were analyzed via X-ray diffraction (XRD), photoluminescence (PL), and afterglow attenuation curves. The outcomes demonstrate that the kind of crystal structure and the location of the emission peak were unaffected by the addition of ions. The addition of Eu2+ to the matrix's lattice caused a broad green emission with a central wavelength of 508 nm, which was attributed to the characteristic 4f65d1 to 4f7 electronic dipole, which allowed the transition of Eu2+ ions. While acting as sensitizers, Dy3+ and Gd3+ could produce holes to create a trap energy level, which served as an electron trap center to catch some of the electrons produced by the excitation of Eu2+ but did not itself emit light. After excitation ceased, this allowed them to gently transition to the ground state to produce long-afterglow luminescence. It was observed that with the addition of sensitizer ions, the luminous intensity of the sample increased, and the afterglow duration lengthened. The elemental structure and valence states of the doped ions were determined with an X-ray photoelectron spectrometer (XPS). Scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX) were used to characterize the samples. The results show that the sample was synthesized successfully, and the type and content of ions in the fluorescent powder could be determined. The fluorescence lifetime, quantum yield, bandgap value, afterglow decay time, and coordinate position in the coherent infrared energy (CIE) diagram of the three best sample groups were then analyzed and compared. Combining the prepared phosphor with ink provides a new idea and method for the field of anti-counterfeiting through screen printing.

Urban greenspace types influence the microbial community assembly and antibiotic resistome more in the phyllosphere than in the soil.

Urban greenspace (UGS) is recognized to confer significant societal benefits, but few studies explored the microbial communities and antibiotic resistance genes (ARGs) from different urban greenspace types. Here, we collected leaf and soil samples from forest, greenbelt, and parkland to analyze microbial community assembly and ARG profile. For phyllosphere fungal community, the α-diversity was higher in forest, compared to those in greenbelt and parkland. Moreover, urban greenspace types altered the community assembly. Stochastic processes had a greater effect on phyllosphere fungal community in greenbelt and parkland, while in forest they were dominated by deterministic processes. In contrast, no significant differences in bacterial community diversity, community assembly were observed between the samples collected from different urban greenspace types. A total of 153 ARGs and mobile genetic elements (MGEs) were detected in phyllosphere and soil with resistance to the majority classes of antibiotics commonly applied to humans and animals. Structural equation model further revealed that a direct association between greenspace type and ARGs in the phyllosphere even after considering the effects of all other factors simultaneously. Our findings provide new insights into the microbial communities and antibiotic resistome of urban greenspaces and the potential risk linked with human health.

Effects of gut microbiota on omega-3-mediated ovary and metabolic benefits in polycystic ovary syndrome mice.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder that frequently exhibits low-grade inflammation, pro-oxidant activity, and gut dysbiosis. PCOS has become one of the leading causes of female infertility worldwide. Recently, omega-3 polyunsaturated fatty acids (PUFAs) have been proven to benefit metabolic disorders in PCOS patients. However, its roles in the regulation of metabolic and endocrinal balances in PCOS pathophysiology are not clear. In the present study, we aimed to explore how omega-3 PUFAs alleviate ovarian dysfunction and insulin resistance in mice with dehydroepiandrosterone (DHEA)-induced PCOS by modulating the gut microbiota. METHODS: We induced PCOS in female mice by injecting them with DHEA and then treated them with omega-3 PUFAs. 16S ribosomal DNA (rDNA) amplicon sequencing, fecal microbiota transplantation (FMT) and antibiotic treatment were used to evaluate the role of microbiota in the regulation of ovarian functions and insulin resistance (IR) by omega-3 PUFAs. To further investigate the mechanism of gut microbiota on omega-3-mediated ovarian and metabolic protective effects, inflammatory and oxidative stress markers in ovaries and thermogenic markers in subcutaneous and brown adipose tissues were investigated. RESULTS: We found that oral supplementation with omega-3 PUFAs ameliorates the PCOS phenotype. 16S rDNA analysis revealed that omega-3 PUFA treatment increased the abundance of beneficial bacteria in the gut, thereby alleviating DHEA-induced gut dysbiosis. Antibiotic treatment and FMT experiments further demonstrated that the mechanisms underlying omega-3 benefits likely involve direct effects on the ovary to inhibit inflammatory cytokines such as IL-1ß, TNF-α and IL-18. In addition, the gut microbiota played a key role in the improvement of adipose tissue morphology and function by decreasing multilocular cells and thermogenic markers such as Ucp1, Pgc1a, Cited and Cox8b within the subcutaneous adipose tissues. CONCLUSION: These findings indicate that omega-3 PUFAs ameliorate androgen-induced gut microbiota dysbiosis. The gut microbiota plays a key role in the regulation of omega-3-mediated IR protective effects in polycystic ovary syndrome mice. Moreover, omega-3 PUFA-regulated improvements in the ovarian dysfunction associated with PCOS likely involve direct effects on the ovary to inhibit inflammation. Our findings suggest that omega-3 supplementation may be a promising therapeutic approach for the treatment of PCOS by modulating gut microbiota and alleviating ovarian dysfunction and insulin resistance.

Reduction-responsive nucleic acid nanocarrier-mediated miR-22 inhibition of PI3K/AKT pathway for the treatment of patient-derived tumor xenograft osteosarcoma.

miRNAs are important regulators of gene expression and play key roles in the development of cancer, including osteosarcoma. During the development of osteosarcoma, the expression of miR-22 is significantly downregulated, making miR-22 as a promising therapeutic target against osteosarcoma. To design and fabricate efficient delivery carriers of miR-22 into osteosarcoma cells, a hydroxyl-rich reduction-responsive cationic polymeric nanoparticle, TGIC-CA (TC), was developed in this work, which also enhanced the therapeutic effects of Volasertib on osteosarcoma. TC was prepared by the ring-opening reaction between amino and epoxy groups by one-pot method, which had the good complexing ability with nucleic acids, reduction-responsive degradability and gene transfection performance. TC/miR-22 combined with volasertib could inhibit proliferation, migration and promote apoptosis of osteosarcoma cells in vitro. The anti-tumor mechanisms were revealed as TC/miR-22 and volasertib could inhibit the PI3K/Akt signaling pathway synergistically. Furthermore, this strategy showed outstanding tumor suppression performance in animal models of orthotopic osteosarcoma, especially in patient-derived chemo-resistant and chemo-intolerant patient-derived xenograft (PDX) models, which reduced the risk of tumor lung metastasis and overcame drug resistance. Therefore, it has great potential for efficient treatment of metastasis and drug resistance of osteosarcoma by the strategy of localized, sustained delivery of miR-22 using the cationic nanocarriers combined with non-traditional chemotherapy drugs.