Advancement and Applications of Nanotherapy for Cancer Immune Microenvironment

Cancer treatment has evolved rapidly due to major advances in tumor immunity research.However,due to the complexity,heterogeneity,and immunosuppressive microenvir-onment of tumors,the overall efficacy of immunotherapy is only 20%.In recent years,nanoparticles have attracted more attention in the field of cancer immunotherapy because of their remarkable advantages in biocompatibility,precise targeting,and controlled drug delivery.However,the clinical application of nanomedicine also faces many problems concerning biological safety,and the synergistic mechanism of nano-drugs with immunity remains to be elucidated.Our study summarizes the functional characteristics and regulatory mechanisms of nanoparticles in the cancer immune microenvironment and how nanoparticles activate and long-term stimulate innate immunity and adaptive immunity.Finally,the current problems and future development trends regarding the application of nanoparticles are fully discussed and prospected to promote the transformation and application of nanomedicine used in cancer treatment.

Nano-revolution in hepatocellular carcinoma:A multidisciplinary odyssey-Are we there yet?

In this editorial we comment on the review by Zhou et al reviewing the landscape of nanomedicine in the treatment of hepatocellular carcinoma(HCC).We focus on the immense potential of nanotechnology,particularly ligand-receptor mediated nanotherapy,in revolutionizing the treatment landscape of HCC.Despite advan-cements in multidisciplinary treatment,HCC remains a significant global health challenge.Ligand-mediated nanotherapy offers the opportunity for precise drug delivery to tumor sites,targeting specific receptors overexpressed in HCC cells,thereby enhancing efficacy and minimizing side effects.Overcoming drug resistance and aggressive tumor biology is facilitated by nanomedicine,bypassing traditional hurdles encountered in chemotherapy.Examples include targeting glypican-3,asialoglycoprotein,transferrin receptor or folic acid receptors,capitalizing on their over-expression in tumor cells.The ability for multi-receptor targeting through dual-ligand nanoparticle modification holds the prospect of further enhancement in specificity and efficacy of directed therapy.However,challenges including immune responses,reproducibility in nanoparticle synthesis,and production scalability remain.Future directions involve refining targeting strategies,improving drug release mechanisms,and streamlining production processes to enable personalized and multifunctional nanotherapies.Overall,the integration of nanotherapy in HCC treatment holds immense promise,but continued partnership and effort are needed in offering hope for more effective,precise,and accessible clinical care in the management of HCC.

Bioresponsive nanotherapy for preventing dental caries by inhibiting multispecies cariogenic biofilms

Early childhood caries(ECC)is a public healthcare concern that greatly reduces the quality of life of young children.As a leading factor of ECC,cariogenic biofilms are composed of acidogenic/aciduric pathogens and extracellular polysaccharides(EPSs),creating an acidic and protected microenvironment.Antimicrobial photodynamic therapy(aPDT)is a noninvasive,painless,and efficient therapeutic approach that is suitable for treating ECC.However,due to the hyperfine structure of cariogenic biofilms,most photosensitizers(PSs)could not access and penetrate deeply in biofilms,which dramatically hamper their efficiency in the clinic.Herein,bioresponsive nanoparticle loaded with chlorin e6(MPP-Ce6)is developed,which largely increases the penetration depth(by over 75%)and retention(by over 100%)of PS in the biofilm compared with free Ce6.Furthermore,MPP-Ce6-mediated aPDT not only kills the bacteria in preformed biofilms but also inhibits multispecies biofilm formation.A rampant caries model is established to mimic ECC in vivo,where the population of cariogenic bacteria is decreased to 10%after MPP-Ce6-mediated aPDT.Importantly,the number and severity of carious lesions are efficiently reduced via Keyes’scoring and micro-CT analysis.This simple but effective strategy can serve as a promising approach for daily oral hygiene in preventing ECC.

Therapeutic Potential of Neem Synthesized Silver Nanoparticles on Human Gastric Cancer Cells in Vitro

Nanotechnology has shown significant promise in development of drugs and drug delivery systems that can overcome all limitations and address urgent needs to improve efficacy of diagnosis and therapy of various diseases including cancer. The functionalization with neem compounds as synthesis and capping agent had shown very high anticancer activities against Gastric cancer cells in vitro. The biochemical factors like albumin, glucose, and DNA concentrations were modulated along with Protease inhibitor and Catalase activates, the various cancer specific proteins like p53, GRD 70 - 78 kDa and other proteins of sizes 35 - 40 kDa corresponding to H+K+ATPase protein etc. The apoptic activity and antiproliferative activity were demonstrated with Gastric cancer cells in vitro.

A combined nanotherapeutic approach targeting farnesoid X receptor,ferroptosis,and fibrosis for nonalcoholic steatohepatitis treatment

Obeticholic acid(OCA),a farnesoid X receptor(FXR)agonist with favorable effects on fatty and glucose metabolism,has been considered the leading candidate drug for nonalcoholic steatohepatitis(NASH)treatment.However,its limited effectiveness in resolving liver fibrosis and lipotoxicity-induced cell death remains a major drawback.Ferroptosis,a newly recognized form of cell death characterized by uncontrolled lipid peroxidation,is involved in the progression of NASH.Nitric oxide(NO)is a versatile biological molecule that can degrade extracellular matrix.In this study,we developed a PEGylated thiolated hollow mesoporous silica nanoparticles(MSN)loaded with OCA,as well as a ferroptosis inhibitor liproxsatin-1 and a NO donor S-nitrosothiol(ONL@MSN).Biochemical analyses,histology,multiplexed flow cytometry,bulk-tissue RNA sequencing,and fecal 16S ribosomal RNA sequencing were utilized to evaluate the effects of the combined nanoparticle(ONL@MSN)in a mouse NASH model.Compared with the OCA-loaded nanoparticles(O@MSN),ONL@MSN not only protected against hepatic steatosis but also greatly ameliorated fibrosis and ferroptosis.ONL@MSN also displayed enhanced therapeutic actions on the maintenance of intrahepatic macrophages/monocytes homeostasis,inhibition of immune response/lipid peroxidation,and correction of microbiota dysbiosis.These findings present a promising synergistic nanotherapeutic strategy for the treatment of NASH by simultaneously targeting FXR,ferroptosis,and fibrosis.

Perfluoropentane-based oxygen-loaded nanodroplets reduce microglial activation through metabolic reprogramming

Microglia,the primary immune cells within the brain,have gained recognition as a promising therapeutic target for managing neurodegenerative diseases within the central nervous system,including Parkinson’s disease.Nanoscale perfluorocarbon droplets have been reported to not only possess a high oxygen-carrying capacity,but also exhibit remarkable anti-inflammatory properties.However,the role of perfluoropentane in microglia-mediated central inflammatory reactions remains poorly understood.In this study,we developed perfluoropentane-based oxygen-loaded nanodroplets(PFP-OLNDs)and found that pretreatment with these droplets suppressed the lipopolysaccharide-induced activation of M1-type microglia in vitro and in vivo,and suppressed microglial activation in a mouse model of Parkinson’s disease.Microglial suppression led to a reduction in the inflammatory response,oxidative stress,and cell migration capacity in vitro.Consequently,the neurotoxic effects were mitigated,which alleviated neuronal degeneration.Additionally,ultrahigh-performance liquid chromatography–tandem mass spectrometry showed that the anti-inflammatory effects of PFP-OLNDs mainly resulted from the modulation of microglial metabolic reprogramming.We further showed that PFP-OLNDs regulated microglial metabolic reprogramming through the AKT-mTOR-HIF-1αpathway.Collectively,our findings suggest that the novel PFP-OLNDs constructed in this study alleviate microglia-mediated central inflammatory reactions through metabolic reprogramming.

Pathologically triggered in situ aggregation of nanoparticles for inflammation-targeting amplification and therapeutic potentiation

Uncontrolled and persistent inflammation is closely related to numerous acute and chronic diseases.However,effective targeting delivery systems remain to be developed for precision therapy of inflammatory diseases.Herein we report a novel strategy for engineering inflammationaccumulation nanoparticles via phenolic functionalization.Different phenol-functionalized nanoparticles were first developed,which can undergo in situ aggregation upon triggering by the inflammatory/oxidative microenvironment.Phenolic compound-decorated poly(lactide-co-glycolide)nanoparticles,in particular tyramine(Tyr)-coated nanoparticles,showed significantly enhanced accumulation at inflammatory sites in mouse models of colitis,acute liver injury,and acute lung injury,mainly resulting from in situ cross-linking and tissue anchoring of nanoparticles triggered by local myeloperoxidase and reactive oxygen species.By combining a cyclodextrin-derived bioactive material with Tyr decoration,a multifunctional nanotherapy(TTN)was further developed,which displayed enhanced cellular uptake,antiinflammatory activities,and inflammatory tissue accumulation,thereby affording amplified therapeutic effects in mice with colitis or acute liver injury.Moreover,TTN can serve as a bioactive and inflammation-targeting nanoplatform for site-specifically delivering a therapeutic peptide to the inflamed colon post oral administration,leading to considerably potentiated in vivo efficacies.Preliminary studies also revealed good safety of orally delivered TTN.Consequently,Tyr-based functionalization is promising for inflammation targeting amplification and therapeutic potentiation of nanotherapies.

Intrinsically bioactive and biomimetic nanoparticle-derived therapies alleviate asthma by regulating multiple pathological cells

Asthma is a serious global public health concern. Airway neutrophilic inflammation is closely related to severe asthma, for which effective and safe therapies remain to be developed. Here we report nanotherapies capable of simultaneously regulating multiple target cells relevant to the pathogenesis of neutrophilic asthma. A nanotherapy LaCD NP based on a cyclic oligosaccharide-derived bioactive material was engineered. LaCD NP effectively accumulated in the injured lungs of asthmatic mice and mainly distributed in neutrophils, macrophages, and airway epithelial cells after intravenous or inhalation delivery, thereby ameliorating asthmatic symptoms and attenuating pulmonary neutrophilic inflammation as well as reducing airway hyperresponsiveness, remodeling, and mucus production. Surface engineering via neutrophil cell membrane further enhanced targeting and therapeutic effects of LaCD NP. Mechanistically, LaCD NP can inhibit the recruitment and activation of neutrophils, especially reducing the neutrophil extracellular traps formation and NLRP3 inflammasome activation in neutrophils. Also, LaCD NP can suppress macrophage-mediated pro-inflammatory responses and prevent airway epithelial cell death and smooth muscle cell proliferation, by mitigating neutrophilic inflammation and its direct effects on relevant cells. Importantly, LaCD NP showed good safety performance. Consequently, LaCD-derived multi-bioactive nanotherapies are promising for effective treatment of neutrophilic asthma and other neutrophil-associated diseases.