A PET probe targeting polyamine transport system for precise tumor diagnosis and therapy

Polyamine metabolism dysregulation is a hallmark of many cancers,offering a promising avenue for early tumor theranostics.This study presents the development of a nuclear probe derived from spermidine(SPM)for dual-purpose tumor PET imaging and internal radiation therapy.The probe,radiolabeled with either[68Ga]Ga for diagnostic applications or[177Lu]Lu for therapeutic use,was synthesized with exceptional purity,stability,and specific activity.Extensive testing involving 12 different tumor cell lines revealed remarkable specificity towards B16 melanoma cells,showcasing outstanding tumor localization and target-to-non-target ratio.Mechanistic investigations employing polyamines,non-labeled precursor,and polyamine transport system(PTS)inhibitor,consistently affirmed the probe?s targetability through recognition of the PTS.Notably,while previous reports indicated PTS upregulation in various tumor types for targeted therapy,this study observed no positive signals,highlighting a concentration-dependent discrepancy between targeting for therapy and diagnosis.Furthermore,when labeled with[177Lu],the probe demonstrated its therapeutic potential by effectively controlling tumor growth and extending mouse survival.Investigations into biodistribution,excretion,and biosafety in healthy humans laid a robust foundation for clinical translation.This study introduces a versatile SPM-based nuclear probe with applications in precise tumor theranostics,offering promising prospects for clinical implementation.

Mn-based cGAS-STING activation for tumor therapy

Immunotherapy has efficiently revolutionized the treatment of human neoplastic diseases.However,the overall responsive rate of current immunotherapy is still unsatisfactory,benefiting only a small proportion of patients.Therefore,significant attention has been paid to the modulation of tumor microenvironment(TME)for the enhancement of immunotherapy.Interestingly,recent studies have shown that cyclic GMP-AMP synthasestimulator of interferon gene(cGAS-STING)was initially found as an innate immune sensor to recognize cytoplasmic DNA(such as bacterial,viral,micronuclei,and mitochondrial).It is a promising signaling pathway to activate antitumor immune responses via type I interferon production.Notably,Mn^(2+)was found to be a critical molecule to sensitize the activation of the cGAS-STING pathway for better immunotherapy.This activation led to the development of Mn^(2+)-based strategies for tumor immunotherapy via the activation of the cGAS-STING pathway.In this critical review,we aimed to summarize the recent progress of this field,focusing on the following three aspects.First,we briefly introduced the signaling pathway of cGAS-STING activation,and its regulation effect on the antitumor immunity cycle has been discussed.Along with this,several agonists of the cGAS-STING pathway were introduced with their potential as immunotherapeutic drugs.Then,the basic biological functions of Mn^(2+)have been illustrated,focusing on its critical roles in the cGAS-STING pathway activation.Next,we systematically reviewed the Mn^(2+)-based strategies for tumor immunotherapy,which can be classified by the methods based on Mn^(2+)alone or Mn^(2+)combined with other therapeutic modalities.We finally speculated the future perspectives of the field and provided rational suggestions to develop better Mn^(2+)-based therapeutics.

Fenton metal nanomedicines for imaging-guided combinatorial chemodynamic therapy against cancer

Chemodynamic therapy(CDT)is considered as a promising modality for selective cancer therapy,which is realized via Fenton reaction-mediated decomposition of endogenous H_(2)O_(2) to produce toxic hydroxyl radical(•OH)for tumor ablation.While extensive efforts have been made to develop CDT-based therapeutics,their in vivo efficacy is usually unsatisfactory due to poor catalytic activity limited by tumor microenvironment,such as anti-oxidative systems,insufficient H_(2)O_(2),and mild acidity.To mitigate these issues,we have witnessed a surge in the development of CDT-based combinatorial nanomedicines with complementary or synergistic mechanisms for enhanced tumor therapy.By virtue of their bio-imaging capabilities,Fenton metal nanomedicines(FMNs)are equipped with intrinsic properties of imaging-guided tumor therapies.In this critical review,we summarize recent progress of this field,focusing on FMNs for imaging-guided combinatorial tumor therapy.First,various Fenton metals with inherent catalytic performances and imaging properties,including Fe,Cu and Mn,were introduced to illustrate their possible applications for tumor theranostics.Then,CDT-based combinatorial systems were reviewed by incorporating many other treatment means,including chemotherapy,photodynamic therapy(PDT),sonodynamic therapy(SDT),photothermal therapy(PTT),starvation therapy and immunotherapy.Next,various imaging approaches based on Fenton metals were presented in detail.Finally,challenges are discussed,and future prospects are speculated in the field to pave way for future developments.

Non-cytotoxic nanoparticles re-educating macrophages achieving both innate and adaptive immune responses for tumor therapy

Macrophages are important antigen-presenting cells to combat tumor via both innate and adaptive immunity,while they are programmed toM2 phenotype in established tumors and instead promote cancer development and metastasis.Here,we develop a nanomedicine that can re-educate M2 polarized macrophages to restore their anti-tumor activities.The nanomedicine has a core-shell structure to co-load IPI549,a PI3Kγinhibitor,and CpG,a Toll-like receptor 9 agonist.Specifically,the hydrophobic IPI549 is self-assembled into a pure drug nano-core,while MOF shell layer is coated for CpG encapsulation,achieving extra-high total drugs loading of 44%.Such nanosystem could facilitate intracellular delivery of the payloads but without any cytotoxicity,displaying excellent biocompatibility.After entering macrophages,the released IPI549 and CpG exert a synergistic effect to switch macrophages from M2 to M1 phenotype,which enables anti-tumor activities via directly engulfing tumor cells or excreting tumor killing cytokines.Moreover,tumor antigens released from the dying tumor cells could be effectively presented by the re-educated macrophages owing to the up-regulation of various antigen presenting mediators,resulting in infiltration and activation of cytotoxic T lymphocytes.As a result,the nanosystem triggers a robust antitumor immune response in combination with PD-L1 antibody to inhibit tumor growth and metastasis.This work provides a non-cytotoxic nanomedicine to modulate tumor immune microenvironment by reprograming macrophages.

Repurposing disulfiram with CuET nanocrystals:Enhancing anti-pyroptotic effect through NLRP3 inflammasome inhibition for treating inflammatory bowel diseases

Drug repurposing offers a valuable strategy for identifying new therapeutic applications for existing drugs.Recently,disulfiram(DSF),a drug primarily used for alcohol addiction treatment,has emerged as a potential treatment for inflammatory diseases by inhibiting pyroptosis,a form of programmed cell death.The therapeutic activity of DSF can be further enhanced by the presence of Cu^(2+),although the underlying mechanism of this enhancement remains unclear.In this study,we investigated the mechanistic basis of Cu^(2+)-induced enhancement and discovered that it is attributed to the formation of a novel copper ethylthiocarbamate(CuET)complex.CuET exhibited significantly stronger anti-pyroptotic activity compared to DSF and employed a distinct mechanism of action.However,despite its potent activity,CuET suffered from poor solubility and limited permeability,as revealed by our druggability studies.To overcome these intrinsic limitations,we developed a scalable method to prepare CuET nanocrystals(CuET NCs)using a metal coordination-driven self-assembly approach.Pharmacokinetic studies demonstrated that CuET NCs exhibited a 6-fold improvement in bioavailability.Notably,CuET NCs exhibited high biodistribution in the intestine,suggesting their potential application for the treatment of inflammatory bowel diseases(IBDs).To evaluate their therapeutic efficacy in vivo,we employed a murine model of DSS-induced colitis and observed that CuET NCs effectively attenuated inflammation and ameliorated colitis symptoms.Our findings highlight the discovery of CuET as a potent anti-pyroptotic agent,and the development of CuET NCs represents a novel approach to enhance the druggability of CuET.

Harnessing bacteria for tumor therapy:Current advances and challenges

After a century of standstill,bacteria-based tumor therapy has resurged recently benefiting from the revolution of tumor immunotherapy,which provides unique solutions to tackle the obstacles of traditional tumor treatments.Obligate and facultative anaerobes with active tropism can selectively colonize at tumor sites and suppress tumor growth via different mechanisms,serving as attractive tools for tumor treatment either as a monotherapy or combining with other therapies for synergistic anti-tumor effects.In this critical review,we introduce the recent advances of bacteria-based tumor therapy from the following aspects.First,the general properties of bacteria are reviewed emphasizing on their structural components related to tumor immunotherapy,and the main bacteria that have been used in tumor therapy are listed.Then,the benefits of bacteria for tumor therapy are illustrated,such as tumor targetability,deep penetration,and facile genetic engineering for attenuation,enhanced efficacy,as well as bioimaging.Next,anti-tumor mechanisms of bacteria are summarized,which refer to intrinsic tumoricidal activities,immune activation,bacteria metabolism,and their capability to regulate gut microbiota homeostasis.Moreover,bacteria could act as carriers to deliver various types of therapeutics to achieve combination therapy with improved efficacy.In addition,several challenges for anti-tumor applications of bacteria are discussed regarding the delivery,efficacy and safety issues,and potential solutions are also provided.Finally,the possible improvements and perspectives are discussed in the end,which provide a guideline for the design of advanced bacteria-based tumor therapeutics in the future.

Activable Photodynamic DNA Probe with an“AND”Logic Gate for Precision Skin Cancer Therapy

Photodynamic therapy(PDT)has emerged as a promising approach for squamous cell carcinoma treatment but hindered by tumor hypoxia,acquired resistance,phototoxicity,and so on.To address these issues,we developed a smart strategy utilizing activable photosensitizers delivered by an aptamer-functionalized DNA probe(ADP).The ADP incorporated an AS1411 aptamer for tumor targeting and a linear antisense oligonucleotide(ASO)for recognition of Survivin mRNA.In the absence of the target,PDT remained quenched,thereby avoiding phototoxicity during circulation and nonselective distribution.With the aid of the aptamer,ADP achieved selective targeting of tumors.Upon internalization,ADP targeted recognized Survivin mRNA,triggering PDT activation,and releasing ASO to down-regulate Survivin expression and reverse tumor resistance.Consequently,the activable photosensitizers exhibited an“AND”logic gate,combining tumor-targeting delivery and tumor-related gene activation,thus enhancing its specificity.Additionally,the incorporation of hemin into the ADP provided catalase activity,converting tumor-abundant H_(2)O_(2) into O_(2),thereby ameliorating tumor hypoxia.The resulting functionalized G-quadruplex/hemin–DNA probe complex demonstrated targeted delivery and activation,minimized side effects,and enhanced PDT efficacy in both xenograft tumor-bearing mice and patient-derived xenograft models.This study offers a unique and promising platform for efficient and safe PDT,thus holding great potential for future clinical translation and improved cancer therapy.

Recent progress of vaccines administration via microneedles for cancer immunotherapy

Therapeutic cancer vaccines have undergone a resurgence in the past decade.Because of the high level of immune cell accumulation and abundant capillary lymphatic system in the dermis,percutaneous vaccination is considered to be an ideal treatment route.For convenient administration,the recent development of microneedles(MNs)provides a safe,painless,and low-cost transdermal delivery strategy,which could bypass the first-pass metabolism of vaccines for enhanced stability and bioavailability.However,the therapeutic effect of MNs-based cancer vaccines is not optimal,which is limited by the complex set of host,tumor,and environmental factors,as well as the limited vaccine loading capacity.Therefore,further improvements are still required to push their clinical translation.In this critical review,we deliberate on how to improve the therapeutic effect of MNs-based vaccines for cancer immunotherapy,summarize the recent advances in MNs-based cancer vaccination,and provide an overview of various design strategies and mechanisms for active or passive targeting delivery,aiming to develop safer,more effective,and more stable MNs-based cancer vaccines.Finally,we briefly describe the potential of vaccine platforms in combination with other therapies,suggest the need to design vaccines according to specific circumstances,and discuss the biosafety of repeated administration for enhancing clinical efficacy.

Advances of nanoparticles as drug delivery systems for disease diagnosis and treatment

Decades have passed since the first nanoparticles-base medicine was approved for human cancer treatment, and the research and development of nanoparticles for drug delivery are always undergoing.Nowadays, the significant advances complicate nanoparticles’ branches, including liposomes, solid lipid nanoparticles, inorganic nanoparticles, micelles, nanovaccines and nano-antibodies, etc. These nanoparticles show numerous capabilities in treatment and diagnosis of stubborn diseases like cancer and neurodegenerative diseases, emerging as novel drug carriers or therapeutic agents in future. In this review, the complicated branches of nanoparticles are classified and summarized, with their property and functions concluded. Besides, there are also some delivery strategies that make nanoparticles smarter and more efficient in drug delivery, and frontiers in these strategies are also summarized in this review. Except these excellent works in newly-produced drug delivery nanoparticles, some points of view and future expectations are made in the end.

Salmonella-mediated blood-brain barrier penetration,tumor homing and tumor microenvironment regulation for enhanced chemo/bacterial glioma therapy

Chemotherapy is an important adjuvant treatment of glioma,while the efficacy is far from satisfactory,due not only to the biological barriers of blood-brain barrier(BBB)and blood-tumor barrier(BTB)but also to the intrinsic resistance of glioma cells via multiple survival mechanisms such as upregulation of P-glycoprotein(P-gp).To address these limitations,we report a bacteria-based drug delivery strategy for BBB/BTB transportation,glioma targeting,and chemo-sensitization.Bacteria selectively colonized into hypoxic tumor region and modulated tumor microenvironment,including macrophages repolarization and neutrophils infiltration.Specifically,tumor migration of neutrophils was employed as hitchhiking delivery of doxorubicin(DOX)-loaded bacterial outer membrane vesicles(OMVs/DOX).By virtue of the surface pathogen-associated molecular patterns derived from native bacteria,OMVs/DOX could be selectively recognized by neutrophils,thus facilitating glioma targeted delivery of drug with significantly enhanced tumor accumulation by 18-fold as compared to the classical passive targeting effect.Moreover,the P-gp expression on tumor cells was silenced by bacteria typeⅢsecretion effector to sensitize the efficacy of DOX,resulting in complete tumor eradication with 100%survival of all treated mice.In addition,the colonized bacteria were finally cleared by anti-bacterial activity of DOX to minimize the potential infection risk,and cardiotoxicity of DOX was also avoided,achieving excellent compatibility.This work provides an efficient trans-BBB/BTB drug delivery strategy via cell hitchhiking for enhanced glioma therapy.

Converting bacteria into autologous tumor vaccine via surface biomineralization of calcium carbonate for enhanced immunotherapy

Autologous cancer vaccine that stimulates tumor-specific immune responses for personalized immunotherapy holds great potential for tumor therapy.However,its efficacy is still suboptimal due to the immunosuppressive tumor microenvironment(ITM).Here,we report a new type of bacteria-based autologous cancer vaccine by employing calcium carbonate(CaCO_(3))biomineralized Salmonella(Sal)as an in-situ cancer vaccine producer and systematical ITM regulator.CaCO_(3) can be facilely coated on the Sal surface with calcium ionophore A23187 co-loading,and such biomineralization did not affect the bioactivities of the bacteria.Upon intratumoral accumulation,the CaCO_(3) shell was decomposed at an acidic microenvironment to atenuate tumor acidity,accompanied by the release of Sal and Ca^(2+)/A23187.Specifically,Sal served as a cancer vaccine producer by inducing cancer cells'immunogenic cell death(ICD)and promoting the gap junction formation between tumor cells and dendritic cells(DCs)to promote antigen presentation.Ca^(2+),on the other hand,was intermalized into various types of immune cells with the aid of A23187 and synergized with Sal to systematically regulate the immune system,including DCs maturation,macrophages polarization,and T cells activation.As a result,such bio-vaccine achieved remarkable effcacy against both primary and metastatic tumors by eliciting potent anti-tumor immunity with full biocompatibility.This work demonstrated the potential of bioengineered bacteria as bio-active vaccines for enhanced tumor immunotherapy.

Macrophages-regulating nanomedicines for sepsis therapy

Sepsis is the leading cause of death in intensive care unit(ICU), which is caused by deregulated immune responses to pathogens infection. Clinically, sepsis treatment is limited to antibiotics and supportive care, while there still lacks of specific molecular therapy. As a type of immune dysfunction disease,macrophages have been recognized as the key immune cells precipitating in the whole process of sepsis,which is activated into M1-like to trigger various inflammatory responses at early stage whereas polarized into M2-like to cause immunosuppression in later stage. Therefore, great attention has been paid on the design of nanomedicines to regulate the functions of macrophages for etiological treatment of sepsis, by virtue of the unique advantages of nano-drug delivery systems, such as enhanced drug bioavailability, targetability, reduced side-effects. This critical review aims to summarize the recent progress of macrophages-regulating nanoparticles for sepsis therapy. First, the essential roles of macrophages in the development and progression of sepsis have been introduced, including the positive roles of macrophages to combat infections and dysfunction of macrophages to cause body damages. We then focus our main attention to discuss the nanomedicines with different therapeutic mechanisms corresponding to each stage of sepsis, such as infection blockage, inflammation inhibition, immune functions recovery, as well as multifunctional nanomedicines. Finally, a few limitations of current nanomedicines are highlighted,and future perspective are speculated for potential clinical translation, which might pave the way for the development of macrophages-centered nanomedicines for more effective sepsis therapy.

Copper carbonate nanoparticles as an effective biomineralized carrier to load macromolecular drugs for multimodal therapy

Macromolecular drugs have attracted great interest as biotherapy to cure previously untreatable diseases.For clinical translation,biomacromolecules encounter several common druggability difficulties,such as in vivo instability and poor penetration to cross physiologic barriers,thus requiring sophisticated systems for drug delivery.Inspired by the natural biomineralization via interaction between inorganic ions and biomacromolecules,herein we rationally screened biocompatible transition metals to biomineralize with carbonate for macromolecules loading.Among the metal ions,Cu^(2+)was found to be the best candidate,and its superiority over the widely studied Ca^(2+)minerals was also demonstrated.Capitalized on this finding,copper carbonate nanoparticles were prepared via a simple mixing process to co-load glucose oxidase(GOx)and a HIF-αDNAzyme(DZ),achieving ultra-high loading capacity of 61%.Upon encapsulation into nanoparticles,enzymatic activity of both drugs was passivated to avoid potential side-effects during circulation,while the drugs could be rapidly released within 1 h in response to acidic p H to fully recover their activities.The nanoparticles could accumulate into tumor via intravenous injection,facilitate the cell membrane penetration,and release the payloads of GOx,DZ and Cu^(2+)inside cells to exert a series of anti-tumor effects.GOx caused tumor starvation by catalytic glucose consumption,and the concomitantly generated H_(2)O_(2)byproduct boosted the Cu^(2+)-mediated chemodynamic therapy(CDT).Meanwhile,the DZ silenced HIF-αexpression to sensitize both starvation therapy and CDT.As a result,a synergistic tumor growth inhibition was achieved.This work provides a simple method to prepare biomineralized nanoparticles,and offers a general approach for macromolecular drugs delivery via Cu^(2+)-based biomineralization.

Photothermal Nano-Vaccine Promoting Antigen Presentation and Dendritic Cells Infiltration for Enhanced Immunotherapy of Melanoma via Transdermal Microneedles Delivery

Immunotherapy has demonstrated the potential to cure melanoma,while the current response rate is still unsatisfactory in clinics.Extensive evidence indicates the correlation between the eficacy and pre-existing T-cell in tumors,whereas the baseline T-cell infiltration is lacking in low-response melanoma patients.

A smart MnO_(2)-doped graphene oxide nanosheet for enhanced chemo-photodynamic combinatorial therapy via simultaneous oxygenation and glutathione depletion

The combination of chemotherapy and photodynamic therapy provides a promising approach for enhanced tumor eradication by overcoming the limitations of each individual therapeutic modality.However,tumor is pathologically featured with extreme hypoxia together with the adaptable overexpression of anti-oxidants,such as glutathione(GSH),which greatly restricts the therapeutic efficiency.Here,a combinatorial strategy was designed to simultaneously relieve tumor hypoxia by self-oxygenation and reduce intracellular GSH level to sensitize chemo-photodynamic therapy.In our system,a novel multifunctional nanosystem based on MnO_(2)-doped graphene oxide(GO)was developed to co-load cisplatin(Cis Pt)and a photosensitizer(Ce6).With Mn O_(2)doping,the nanosystem was equipped with intelligent functionalities:(1)catalyzes the decomposition of H_(2)O_(2)into oxygen to relieve the tumor hypoxia;(2)depletes GSH level in tumor cells,and(3)concomitantly generates Mn^(2+)to proceed Fenton-like reaction,all of which contribute to the enhanced anti-tumor efficacy.Meanwhile,the surface hyaluronic acid(HA)modification could facilitate the targeted delivery of the nanosystem into tumor cells,thereby resulting in amplified cellular toxicity,as well as tumor growth inhibition in nude mice model.This work sheds a new light on the development of intelligent nanosystems for synergistic combination therapy via regulating tumor microenvironment.

Smart drug delivery systems for precise cancer therapy

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.

Macrophage-targeted nanomedicine for chronic diseases immunotherapy

Macrophage is the key innate immune effector in first-line defense against the pathogens, and can be polarized into different phenotypes to regulate a variety of immunological functions. However, the plasticity of macrophage is extraordinarily recruited, activated, and polarized under pathological conditions,playing paramount roles in occurrence, development, and prognosis of various chronic diseases, such as rheumatoid arthritis(RA), atherosclerosis(AS), and cancer. To this end, macrophage has become an important therapeutic target for etiological treatment of these diseases. Meanwhile, with the development of nanotechnology, various nano-drug delivery systems have been explored to target macrophages for disease modulation, displaying unique advantages to address both pharmaceutic and biopharmaceutic limitations of various drugs. This review aims to summarize the recent progress of macrophage-targeted nanomedicine for chronic diseases immunotherapy. First, the origin, polarization and biological functions of macrophages have been introduced, in which macrophages can differentiate into different phenotypes in response to physiological stimuli to play various immunological roles. Then, the macrophage disorder has been reviewed in related with various chronic diseases, and several representative diseases, including AS, RA, obesity, and cancer, have been discussed in detail to elucidate the pathological contributions of macrophages for disease progress. Next, strategies to regulate macrophages for diseases immunotherapy, such as macrophages depletion, macrophage reprograming, inhibition of macrophage recruitment,are summarized, and particular attention has been paid on bio-functional nanomaterials to engineer macrophages via different mechanisms. Further, methods for macrophage-targeting delivery nanosystems are discussed based on both passive and active targeting approaches. Finally, the perspective is speculated for potential clinical translation, and there still has significant room for the development of novel macrophage-targeting nanomedicine for precise, effective, and biosafe therapy.