Bimetallic nanoparticles as cascade sensitizing amplifiers for low-dose and robust cancer radio-immunotherapy

Radiotherapy(RT)is one of the most feasible and routinely used therapeutic modalities for treating malignant tumors.In particular,immune responses triggered by RT,known as radio-immunotherapy,can partially inhibit the growth of distantly spreading tumors and recurrent tumors.How-ever,the safety and efficacy of radio-immunotherapy is impeded by the radio-resistance and poor immu-nogenicity of tumor.Herein,we report oxaliplatin(IV)-iron bimetallic nanoparticles(OXA/Fe NPs)as cascade sensitizing amplifiers for low-dose and robust radio-immunotherapy.The OXA/Fe NPs exhibit tumor-specific accumulation and activation of OXA(I)and Fe^(2+)in response to the reductive and acidic microenvironment within tumor cells.The cascade reactions of the released metallic drugs can sensitize RT by inducing DNA damage,increasing ROS and O_(2) levels,and amplifying the immunogenic cell death(ICD)effect after RT to facilitate potent immune activation.As a result,OXA/Fe NPs-based low-dose RT triggered a robust immune response and inhibited the distant and metastatic tumors effectively by a strong abscopal effect.Moreover,a long-term immunological memory effect to protect mice from tumor rechal-lenging is observed.Overall,the bimetallic NPs-based cascade sensitizing amplifier system offers an effi-cient radio-immunotherapy regimen that addresses the key challenges.

Deciphering the high-carbonization-temperature triggered enzymatic activity of wool-derived N,S-co-doped carbon nanosheets

It is well-established that high carbonization temperature will trigger the enzyme-like activity of carbon-based materials.However,the catalytic mechanism is still ambiguous,which hinders the further rational design of nanomaterials as enzyme mimics.Hereby,N,S-rich carbonized wool nanosheets(CWs)were synthesized at different pyrolysis temperatures.As expected,only CWs treated with high-temperature possess intrinsic oxidase-and peroxidase-like activities.Meanwhile,density functional theory(DFT)calculations demonstrate that graphitic nitrogen and the co-existence of nitrogen and sulfur in the carbon matrix serve as the active sites for the enzyme-like process.More importantly,combining theoretical calculations and experimental observations,the high-temperature triggered catalytic mechanism can be ascribed to the fact that an appropriate high-temperature maximizes the graphitization degree to a certain extent,at which most of the catalytic active sites are well retained rather than evaporating.Moreover,coupling with excellent photothermal conversion efficiency and catalytic performance,CWs can be applied to photothermal-catalytic cancer therapy under near-infrared region(NIR)light irradiation.We believe this work will contribute to understanding the catalytic mechanism of carbon-based nanozymes and promote the development of new biomedical and pharmaceutical applications.

Chain-shattering Pt(IV)-backboned polymeric nanoplatform for efficient CRISPR/Cas9 gene editing to enhance synergistic cancer therapy

CRISPR/Cas9 system has become a promising gene editing tool for cancer treatment.However,development of a simple and effective nanocarrier to incorporate CRISPR/Cas9 system and chemotherapeutic drugs to concurrently tackle the biological safety and packaging capacity of viral vectors and combine gene editing-chemo for cancer therapy still remains challenges.Herein,a chain-shattering Pt(IV)-backboned polymeric nanoplatform is developed for the delivery of EZH2-targeted CRISPR/Cas9 system(NPCSPt/pEZH2)and synergistic treatment of prostate cancer.The pEZH2/Pt(II)could be effectively triggered to unpack/release from NPCSPt/pEZH2 in a chain-shattering manner in cancer cells.The EZH2 gene disruption efficiency could be achieved up to 32.2%of PC-3 cells in vitro and 21.3%of tumor tissues in vivo,leading to effective suppression of EZH2 protein expression.Moreover,significant H3K27me3 downregulation could occur after EZH2 suppression,resulting in a more permissive chromatin structure that increases the accessibility of released Pt(II)to nuclear DNA for enhanced apoptosis.Taken together,substantial proliferation inhibition of prostate cancer cells and further 85.4%growth repression against subcutaneous xenograft tumor could be achieved.This chain-shattering Pt(IV)-backboned polymeric nanoplatform system not only provides a prospective nanocarrier for CRISPR/Cas9 system delivery,but also broadens the potential of combining gene editing-chemo synergistic cancer therapy.

Recent advances in polymeric biomaterials-based gene delivery for cartilage repair

Untreated articular cartilage damage normally results in osteoarthritis and even disability that affects millions of people.However,both the existing surgical treatment and tissue engineering approaches are unable to regenerate the original structures of articular cartilage durably,and new strategies for integrative cartilage repair are needed.Gene therapy provides local production of therapeutic factors,especially guided by biomaterials can minimize the diffusion and loss of the genes or gene complexes,achieve accurate spatiotemporally release of gene products,thus provideing long-term treatment for cartilage repair.The widespread application of gene therapy requires the development of safe and effective gene delivery vectors and supportive gene-activated matrices.Among them,polymeric biomaterials are particularly attractive due to their tunable physiochemical properties,as well as excellent adaptive performance.This paper reviews the recent advances in polymeric biomaterial-guided gene delivery for cartilage repair,with an emphasis on the important role of polymeric biomaterials in delivery systems.

Synergistic enhancement of immunological responses triggered by hyperthermia sensitive Pt NPs via NIR laser to inhibit cancer relapse and metastasis

The combination of tumor ablation and immunotherapy is a promising strategy against tumor relapse and metastasis.Photothermal therapy(PTT)triggers the release of tumor-specific antigens and damage associated molecular patterns(DAMPs)in-situ.However,the immunosuppressive tumor microenvironment restrains the activity of the effector immune cells.Therefore,systematic immunomodulation is critical to stimulate the tumor microenvironment and augment the anti-tumor therapeutic effect.To this end,polyethylene glycol(PEG)-stabilized platinum(Pt)nanoparticles(Pt NPs)conjugated with a PD-L1 inhibitor(BMS-1)through a thermo-sensitive linkage were constructed.Upon near-infrared(NIR)exposure,BMS-1 was released and maleimide(Mal)was exposed on the surface of Pt NPs,which captured the antigens released from the ablated tumor cells,resulting in the enhanced antigen internalization and presentation.In addition,the Pt NPs acted as immune adjuvants by stimulating dendritic cells(DCs)maturation.Furthermore,BMS-1 relieved T cell exhaustion and induced the infiltration of effector T cells into the tumor tissues.Thus,Pt NPs can ablate tumors through PTT,and augment the anti-tumor immune response through enhanced antigen presentation and T cells infiltration,thereby preventing tumor relapse and metastasis.

Protein-based biomaterials for combating viral infections:Current status and future prospects for development

The outbreak of viral infections are serious threat to human life and health.However,there remains to be a lack of effective treatments and prophylactic measures against some viral infections.Additionally,there are numerous challenges in developing vaccines and antiviral drugs(e.g.,antibodies and protein inhibitors),such as low immunogenicity of vaccines,difficulties in storing vaccines,instability and easy degradation of protein drugs,and lack of drug selectivity.Protein-based biomaterials can interact with antiviral drugs or vaccines to achieve synergistic or enhanced effects,making them a promising antiviral tool with many advantages.Silk fibroin has the potential to stabilize liquid vaccines at room temperature.Elastin-like polypeptide modification can improve the stability and yield of virus-neutralizing antibodies.Drugs in combination withβ-casein or serum albumin(SA)has good prospects in treating human immunodeficiency virus(HIV)infections.Moreover,the greatest value of SA as a protein-based antiviral material lies in its ability to target the liver and macrophages.In the future,combination with SA(direct conjugation or encapsulation with drugs)may be a better treatment strategy for viral hepatitis and HIV infections because it leads to fewer adverse reactions.In addition,selfassembling protein nanoparticles(SApNPs)are found to improve vaccine immunogenicity.The combination of multiple viral immunogens and multiple SApNPs produces different promising vaccine candidates,thus highlighting the value of SApNPs.This review aimed to discuss the current status and future prospects for the development of protein-based biomaterials to combat viral infections.

Biosafety materials for tuberculosis treatment

Tuberculosis(TB)is among the deadliest infectious diseases worldwide.Although the existing antituberculosis(anti-TB)drugs remain to be effective,the administration of these complex anti-TB drug combinations with obvious toxicity often leads to patients’nonadherence.This may contribute toward the emergence of drug-resistant strains as well as lead to treatment failure and relapse.Therefore,in the past half century,the main focus of anti-TB drug research was to reduce the frequency of administration and toxicity and improve patients’compliance and drug sensitivity.Following these principles,the development of engineered biosafety materials is one of the most effective and promising methods in resolving these challenges.Compared with traditional drugs,biosafety materials provide a viable platform for treating TB,which are beneficial in reducing the frequency of drug administration and systemic toxicity,improving patients’compliance and drug sensitivity,and enhancing drug targeting.In this review,we summarized the application of biosafety materials in treatment of TB in recent years and discussed the challenges faced when developing a safe,more effective,and economical pharmacotherapy against TB.