Edaravone-loaded poly(amino acid) nanogel inhibits ferroptosis for neuroprotection in cerebral ischemia injury

Neurological injury caused by ischemic stroke is a major cause of permanent disability and death. The currently available neuroprotective drugs fail to achieve desired therapeutic efficacy mainly due to short circulation half-life and poor blood−brain barrier (BBB) permeability. For that, an edaravone-loaded pH/glutathione (pH/GSH) dual-responsive poly(amino acid) nanogel (NG/EDA) was developed to improve the neuroprotection of EDA. The nanogel was triggered by acidic and EDA-induced high-level GSH microenvironments, which enabled the selective and sustained release of EDA at the site of ischemic injury. NG/EDA exhibited a uniform sub-spherical morphology with a mean hydrodynamic diameter of 112.3 ± 8.2 nm. NG/EDA efficiently accumulated at the cerebral ischemic injury site of permanent middle cerebral artery occlusion (pMCAO) mice, showing an efficient BBB crossing feature. Notably, NG/EDA with 50 µM EDA significantly increased neuron survival (29.3%) following oxygen and glucose deprivation by inhibiting ferroptosis. In addition, administering NG/EDA for 7 d significantly reduced infarct volume to 22.2% ± 7.2% and decreased neurobehavioral scores from 9.0 ± 0.6 to 2.0 ± 0.8. Such a pH/GSH dual-responsive nanoplatform might provide a unique and promising modality for neuroprotection in ischemic stroke and other central nervous system diseases.

Osteoimmunity-regulating biomaterials promote bone regeneration

Osteoimmunomodulation is a fascinating approach for balancing osteoimmune through regulating reciprocal interactions between bone cells and immune cells[1].Implantation of the osteoimmunity-regulating biomaterials regulates osteoimmune conditions in the host dynamically,thus intensifying osseointegration under physiological microenvironments[1].This perspective presents a brief overview of osteoimmunity-regulating biomaterials for augmenting bone regeneration based on a recently published study by our research team[2].

Nanoantidotes: A Detoxification System More Applicable to Clinical Practice

Since 2010,there has been a much greater awareness of the problem of intoxication,which has become the most common form of accidental and intentional death.In 2020,more than 90,000 people died of intoxication in the United States,which surpassed deaths due to motor vehicle accidents and firearms use to become the leading external cause of mortality.

Role of nanoparticle-mediated immunogenic cell death in cancer immunotherapy

An essential concept of cancer immunotherapy is that immunogenic cell death(ICD),characterized by the release of tumor-associated antigens(TAAs)and tumor-specific antigens(TSAs)like neoantigens,danger-associated molecular patterns(DAMPs),and pro-inflammatory cytokines,facilitates the presentation of TAAs and TSAs to adaptive immune cells,eliciting an emerging or reinstating a pre-existing anti-cancer immune response.

Biointerface engineering nanoplatforms for cancer-targeted drug delivery

Over the past decade,nanoparticle-based therapeutic modalities have become promising strategies in cancer therapy.Selective delivery of anticancer drugs to the lesion sites is critical for elimination of the tumor and an improved prognosis.Innovative design and advanced biointerface engineering have promoted the development of various nanocarriers for optimized drug delivery.Keeping in mind the biological framework of the tumormicroenvironment,biomembrane-camouflaged nanoplatforms have been a research focus,reflecting their superiority in cancer targeting.In this review,we summarize the development of various biomimetic cell membrane-camouflaged nanoplatforms for cancertargeted drug delivery,which are classified according to the membranes fromdifferent cells.The challenges and opportunities of the advanced biointerface engineering drug delivery nanosystems in cancer therapy are discussed.

Calcium ion nanomodulators for mitochondria-targeted multimodal cancer therapy

Various calcium ion(Ca^(2+))nanomodulators are designed for multimodal cancer treatment with the mechanism of intramitochondrial Ca^(2+) overload-induced multilevel mitochondrial destruction.This perspective briefly introduces the development of Ca^(2+) nanomodulators in cancer therapy based on two recent studies published by our research group.

Targeted nanostrategies eliminate pre-metastatic niche of cancer

Establishing a pre-metastatic niche(PMN)in secondary organs is a prerequisite for cancer metastases.Despite advances in cancer therapy,the efficient inhibition of PMN formation remains a clinical challenge.Recent advances in understanding the specific characteristics of PMN and advances in nanotechnology have provided hope for manipulating their microenvironments.A series of nanostrategies have been designed to eliminate the PMN,including the removal of pro-metastatic exosomes from the bloodstream for excretion via the intestines,the targeting and scavenging of myeloid-derived suppressor cells,fibroblasts,and critical extracellular matrix components,and the elimination of circulating tumor cells prior to colonization in distant organs.This review summarizes the underlying mechanisms of PMN formation,highlights the anti-PMN efficacy of currently reported nanostrategies,and underlines the unresolved questions.

A mussel-inspired supramolecular hydrogel with robust tissue anchor for rapid hemostasis of arterial and visceral bleedings

In recent years,the developed hemostatic technologies are still difficult to be applied to the hemostasis of massive arterial and visceral hemorrhage,owing to their weak hemostatic function,inferior wet tissue adhesion,and low mechanical properties.Herein,a mussel-inspired supramolecular interaction-cross-linked hydrogel with robust mechanical property(308.47±29.20 kPa)and excellent hemostatic efficiency(96.5%±2.1%)was constructed as a hemostatic sealant.Typically,we combined chitosan(CS)with silk fibroin(SF)by cross-linking them through tannic acid(TA)to maintain the structural stability of the hydrogel,especially for wet tissue adhesion ability(shear adhesive strength=29.66±0.36 kPa).Compared with other materials reported previously,the obtained CS/TA/SF hydrogel yielded a lower amount of blood loss and shorter time to hemostasis in various arterial and visceral bleeding models,which could be ascribed to the synergistic effect of wound closure under wet state as well as intrinsic hemostatic activity of CS.As a superior hemostatic sealant,the unique hydrogel proposed in this work can be exploited to offer significant advantages in the acute wound and massive hemorrhage with the restrictive access of therapeutic moieties.

Nucleic acid nanoassembly-enhanced RNA therapeutics and diagnosis

RNAs are involved in the crucial processes of disease progression and have emerged as powerful therapeutic targets and diagnostic biomarkers.However,efficient delivery of therapeutic RNA to the targeted location and precise detection of RNA markers remains challenging.Recently,more and more attention has been paid to applying nucleic acid nanoassemblies in diagnosing and treating.Due to the flexibility and deformability of nucleic acids,the nanoassemblies could be fabricated with different shapes and structures.With hybridization,nucleic acid nanoassemblies,including DNA and RNA nanostructures,can be applied to enhance RNA therapeutics and diagnosis.This review briefly introduces the construction and properties of different nucleic acid nanoassemblies and their applications for RNA therapy and diagnosis and makes further prospects for their development.

Immunologically effective poly(D-lactic acid) nanoparticle enhances anticancer immune response

Chiral materials with the same atomic compositions exhibit different chemical,physical,and biological properties because of their distinct spatial structures.Herein,a chiral strategy was proposed to develop poly(lactic acid)(PLA)nanoparticle as an efficient nanoadjuvant to activate adaptive anticancer immunity.Two chiral nanovaccines were prepared by directly mixing amino-terminated PLA(PLLA-NH2 or PDLA-NH2)with the model protein antigen ovalbumin(OVA).After being injected into mice subcutaneously,both nanovaccines efficiently migrated to the lymph nodes to initiate the sequential anticancer immune responses.Compared with the PLLA nanovaccine(PLLA-OVA),the PDLA one(PDLA-OVA)contributed to more robust dendritic cell(DC)maturation,antigen presentation,and T lymphocyte activation.In addition to the activation of cellular immunity,PDLA-OVA also triggered a more vigorous activation of humoral immunity,which induced the production of more anti-OVA immunoglobulin G(IgG)than PLLA-OVA.When used as prophylactic or therapeutic nanovaccine toward murine melanoma models,PDLA-OVA triggered more potent adaptive anticancer immune responses that more effectively inhibited the cancer genesis and progression,indicating the significant potential of immunologically effective PDLA nanoadjuvant in cancer immunotherapy.

Chiral polypeptide nanoparticles as nanoadjuvants of nanovaccines for efficient cancer prevention and therapy

The chirality of bioactive molecules is closely related to their functions.D-amino acids commonly distributed in the bacterial cell walls trigger a robust anti-infective immune response.Inspired by that,two kinds of chiral polypeptides,poly(L-phenylalanine)-block-poly(L-lysine)(PL-K)and poly(Lphenylalanine)-block-poly(D-lysine)(PD-K),were synthesized and used as nanoadjuvants of nanovaccines for cancer prevention and therapy.The amphiphilic polypeptides self-assembled into nanoparticles with a diameter of about 30 nm during ultrasonic-assisted dissolution in phosphate-buffered saline.The nanovaccines PL-K-OVA and PD-K-OVA were easily prepared by mixing solutions of PL-K or PD-K and the model antigen chicken ovalbumin(OVA),respectively,with loading efficiencies of almost 100%.Compared to PL-K-OVA,PD-K-OVA more robustly induced dendritic cell maturation,antigen cross-presentation,and adaptive immune response.More importantly,it effectively prevented and treated the OVA-expressed B16-OVA melanoma model.PD-K-OVA achieved a tumor inhibition rate of 94.9%and even 97.0%by combining with anti-PD-1 antibody.Therefore,the chiral polypeptide nanoparticles represent simple,efficient,and extensively applicable nanoadjuvants for various nanovaccines.

Dentin-desensitizing biomaterials

Dentin hypersensitivity(DH)associated with dentinal tubule exposure is one of the most common causes of toothache with a rapid onset and short duration.Medication,filling repair,laser irradiation,crown therapy,and desensitizing toothpaste are standard clinical treatment strategies,but unsatisfactory treatment modalities are marked by long-term administration,poor dentinal tubule closure,microleakage,and the development of secondary caries.To improve the treatment efficiency of DH,numerous organic or inorganic biomaterials have been developed to relieve toothache and reverse the instability of desensitization.Biomaterials are expected to participate in dental remineralization to achieve desensitization.This review discusses various biomaterials for DH therapy based on different desensitization mechanisms,including dentinal tubule closure and dental nerve blockade,and presents a perspective on the underlying future of dentin regeneration medicine for DH therapy.

Immunologically effective biomaterials-enhanced vaccines against infection of pathogenic microorganisms

Infectious diseases are severe public health events that threaten global health.Prophylactic vaccines have been considered as the most effective strategy to train the immune system to recognize and clear pathogenic infections.However,the existing vaccines against infectious diseases have several limitations,such as difficulties in mass manufacturing and storage,weak immunogenicity,and low efficiency of available adjuvants.Biomaterials,especially functional polymers,are expected to break through these bottlenecks based on the advantages of biocompatibility,degradability,controlled synthesis,easy modification,precise targeting,and immune modulation,which are excellent carriers and adjuvants of vaccines.This review mainly summarizes the application of immunologically effective polymers-enhanced vaccines against viruses-and bacteria-related infectious diseases and predicted their potential improvements.

Functional biomaterials for comprehensive periodontitis therapy

Periodontitis is an inflammatory disease caused by bacterial infection directly, and the dysregulation of host immune-inflammatory response finally destroys periodontal tissues. Current treatment strategies for periodontitis mainly involve mechanical scaling/root planing(SRP), surgical procedures,and systemic or localized delivery of antimicrobial agents. However, SRP or surgical treatment alone has unsatisfactory long-term effects and is easy to relapse. In addition, the existing drugs for local periodontal therapy do not stay in the periodontal pocket long enough and have difficulties in maintaining a steady, effective concentration to obtain a therapeutic effect, and continuous administration always causes drug resistance. Many recent studies have shown that adding bio-functional materials and drug delivery systems upregulates the therapeutic effectiveness of periodontitis. This review focuses on the role of biomaterials in periodontitis treatment and presents an overview of antibacterial therapy, host modulatory therapy, periodontal regeneration, and multifunctional regulation of periodontitis therapy. Biomaterials provide advanced approaches for periodontal therapy, and it is foreseeable that further understanding and applications of biomaterials will promote the development of periodontal therapy.

Controlled Synthesis of Polymers

Controlled synthesis is central to obtaining polymers with accurate structures and excellent performances.Recent research in the controlled synthesis of polymers has focused on optimizing monomers,initiation systems,and reaction conditions.The satisfactory sequence,topological structure,and dispersity have been achieved to satisfy the growing demand for functional polymers.This re-view summarizes the selection of monomers of various types and structures,the innovation of initiation systems,and the optimiza-tion of reaction conditions in the controlled synthesis of polymers and discusses their challenges and opportunities.

靶向肿瘤进化的创新纳米药物

近年来,随着纳米技术的发展,将纳米材料应用于肿瘤靶向治疗有望极大地改善肿瘤治疗效果.纳米药物因其可增加药物溶解性、延长血液循环时间、提高靶向性、提升治疗效果并降低毒副作用等特点而备受研究者关注.肿瘤生物学研究表明,肿瘤始终处于动态的进化和演化过程之中,由于其基因组的不稳定性,肿瘤细胞可在肿瘤内部的生存压力下进行自然选择,或在外来治疗压力(放射治疗、化学治疗、分子靶向治疗和免疫治疗)作用下,持续产生基因突变并扩增,从而导致肿瘤增殖、耐药和转移.因此,肿瘤治疗方案理应随着肿瘤的进化过程而变化和调整.然而,现阶段纳米药物的设计对肿瘤进化的临床现实缺乏充分考虑.本文提出靶向肿瘤进化的创新纳米药物的构想,即从肿瘤进化的临床现实出发,尽可能灵敏地、准确地、全面地跟踪肿瘤在自然选择、治疗压力下出现的增殖、耐药、转移等过程,掌握该过程中的进化特征,并基于这些进化特征设计创新纳米药物,能够有策略地、主动地、及时地动态调整纳米药物及给药方案,结合临床上其他多种治疗药物和方法,力争把肿瘤控制为慢性疾病.

Biomedical applications of mRNA nanomedicine

As an attractive alternative to plasmid DNA, messenger RNA （mRNA） has recently emerged as a promising class of nucleic acid therapeutics for biomedical applications. Advances in addressing the inherent shortcomings of mRNA and in the development of nanoparticle-based delivery systems have prompted the development and clinical translation of mRNA-based medicines. In this review, we discuss the chemical modification strategies of mRNA to improve its stability, minimize immune responses, and enhance translational efficacy. We also highlight recent progress in nanoparticle-based mRNA delivery. Considerable attention is given to the increasingly widespread applications of mRNA nanomedicine in the biomedical fields of vaccination, protein-replacement therapy, gene editing, and cellular reprogramming and engineering.

Poly(lactic-co-glycolic acid)-based composite bone-substitute materials

Research and development of the ideal artificial bone-substitute materials to replace autologous and allogeneic bones for repairing bone defects is still a challenge in clinical orthopedics.Recently,poly(lactic-co-glycolic acid)(PLGA)-based artificial bone-substitute materials are attracting increasing attention as the benefit of their suitable biocompatibility,degradability,mechanical properties,and capabilities to promote bone regeneration.In this article,we comprehensively review the artificial bone-substitute materials made from PLGA or the composites of PLGA and other organic and inorganic substances,elaborate on their applications for bone regeneration with or without bioactive factors,and prospect the challenges and opportunities in clinical bone regeneration.

Engineered three-dimensional scaffolds for enhanced bone regeneration in osteonecrosis

Osteonecrosis,which is typically induced by trauma,glucocorticoid abuse,or alcoholism,is one of the most severe diseases in clinical orthopedics.Osteonecrosis often leads to joint destruction,and arthroplasty is eventually required.Enhancement of bone regeneration is a critical management strategy employed in osteonecrosis therapy.Bone tissue engineering based on engineered three-dimensional(3D)scaffolds with appropriate architecture and osteoconductive activity,alone or functionalized with bioactive factors,have been developed to enhance bone regeneration in osteonecrosis.In this review,we elaborate on the ideal properties of 3D scaffolds for enhanced bone regeneration in osteonecrosis,including biocompatibility,degradability,porosity,and mechanical performance.In addition,we summarize the development of 3D scaffolds alone or functionalized with bioactive factors for accelerating bone regeneration in osteonecrosis and discuss their prospects for translation to clinical practice.

Polypeptide nanoformulation-induced immunogenic cell death and remission of immunosuppression for enhanced chemoimmunotherapy

Many conventional chemotherapeutics play an immune-modulating effect by inducing immunogenic cell death(ICD)in tumor cells.However,they hardly arouse strong antitumor immune response because the immunosuppressive lymphocytes are present in the tumor microenvironment.These immunosuppressive lymphocytes include regulatory T cells(Tregs)and myeloid-derived suppressor cells(MDSCs).We used a low dose of doxorubicin(DOX)to induce ICD in combination with immune regulator 1-methylDL-tryptophan(1 MT)to suppress indoleamine 2,3-dioxygenase and overcome Treg-and MDSCassociated immune suppression.By co-encapsulation of DOX and 1 MT into a reduction-responsive polypeptide nanogel,the drugs were simultaneously released in the tumor cells and synergistically performed antitumor efficacy.After treatment,recruitment of Tregs and MDSCs was inhibited,and the frequency of tumor-infiltrating CD8+T cells was remarkably enhanced.These results demonstrated that the chemoimmunotherapy strategy effectively suppressed tumor growth without causing evident adverse effects,indicating its great potential in clinical cancer therapy.