Upconverting nanoparticle-containing erythrocyte-sized hemoglobin microgels that generate heat,oxygen and reactive oxygen species for suppressing hypoxic tumors

Inspired by erythrocytes that contain oxygen-carrying hemoglobin(Hb)and that exhibit photo-driven activity,we introduce homogenous-sized erythrocyte-like Hb microgel(μGel)systems(5-6μm)that can(i)emit heat,(ii)supply oxygen,and(iii)generate reactive oxygen species(ROS;1O2)in response to near-infrared(NIR)laser irradiation.Hb μGels consist of Hb,bovine serum albumin(BSA),chlorin e6(Ce6)and erbium@lutetium upconverting nanoparticles(UCNPs;~35 nm)that effectively convert 808 nm NIR light to 660 nm visible light.These Hb μGels are capable of releasing oxygen to help generate sufficient reactive oxygen species(^(1)O_(2))from UCNPs/Ce6 under severely hypoxic condition upon NIR stimulation for efficient photodynamic activity.Moreover,the Hb μGels emit heat and increase surface temperature due to NIR light absorption by heme(iron protoporphyrin IX)and display photothermal activity.By changing the Hb/UCNP/Ce6 ratio and controlling the amount of NIR laser irradiation,it is possible to formulate bespoke Hb μGels with either photothermal or photodynamic activity or both in the context of combined therapeutic effect.These Hb μGels effectively suppress highly hypoxic 4T1 cell spheroid growth and xenograft mice tumors in vivo.

STING-activating dendritic cell-targeted nanovaccines that evoke potent antigen cross-presentation for cancer immunotherapy

Recently,nanovaccine-based immunotherapy has been robustly investigated due to its potential in governing the immune response and generating long-term protective immunity.However,the presentation of a tumor peptide-major histocompatibility complex to T lymphocytes is still a challenge that needs to be addressed for eliciting potent antitumor immunity.Type 1 conventional dendritic cell(cDC1)subset is of particular interest due to its pivotal contribution in the cross-presentation of exogenous antigens to CD8+T cells.Here,the DC-derived nanovaccine(denoted as Si9GM)selectively targets cDC1s with marginal loss of premature antigen release for effective stimulator of interferon genes(STING)-mediated antigen cross-presentation.Bone marrow dendritic cell(BMDC)-derived membranes,conjugated to cDC1-specific antibody(αCLEC9A)and binding to tumor peptide(OVA257-264),are coated onto dendrimer-like polyethylenimine(PEI)-grafted silica nanoparticles.Distinct molecular weight-cargos(αCLEC9A-OVA257-264 conjugates and 2′3′-cGAMP STING agonists)are loaded in hierarchical center-radial pores that enables lysosome escape for potent antigen-cross presentation and activates interferon type I,respectively.Impressively,Si9GM vaccination leads to the upregulation of cytotoxic T cells,a reduction in tumor regulatory T cells(Tregs),M1/M2 macrophage polarization,and immune response that synergizes with αPD-1 immune checkpoint blockade.This nanovaccine fulfills a dual role for both direct T cell activation as an artificial antigen-presenting cell and DC subset maturation,indicating its utility in clinical therapy and precision medicine.

Alveolar macrophage phagocytosis-evading inhaled microgels incorporating nintedanib-PLGA nanoparticles and pirfenidone-liposomes for improved treatment of pulmonary fibrosis

Idiopathic pulmonary fibrosis(IPF)is a chronic inflammatory and fibrotic response-driven lung disease that is difficult to cure because it manifests excessive profibrotic cytokines(e.g.,TGF-β),activated myofibroblasts,and accumulated extracellular matrix(ECM).In an attempt to develop an inhalation formulation with enhanced antifibrotic efficacy,we sought to fabricate unique aerosolizable inhaled microgels(μGel)that contain nintedanib-poly(lactic-co-glycolic acid)(PLGA)nanoparticles(NPs;n-PN)and pirfenidone-liposomes(p-LP).The aero-μGel was~12μm,resisted phagocytosis by alveolar macrophages in vitro and in vivo,and protected inner-entrapped n-PN and p-LP.The n-PN/p-LP@aero-μGel caused enhanced/extended antifibrotic efficacy in a bleomycin-induced pulmonary fibrosis mouse presumably due to prolonged lung residence.Consequently,the results obtained by intratracheal aerosol insufflation of our n-PN/p-LP@aero-μGel twice a week were much better than those by as many as seven doses of single or mixed applications of n-PN or p-LP.The antifibrotic/pharmacokinetic results for the n-PN/p-LP@aero-μGel included reduced fibrosis progression,restored lung physiological functions,deactivated myofibroblasts,inhibited TGF-βprogression,and suppressed ECM component production(collagen I andα-SMA)along with prolonged lung retention time.We believe that our n-PN/p-LP@aero-μGel increased the local availability of both nintedanib and pirfenidone due to evasion of alveolar macrophage phagocytosis and prolonged lung retention with reduced systemic distribution.Through this approach,our inhalation formulation subsequently attenuated fibrosis progression and improved lung function.Importantly,these results hold profound implications in the therapeutic potential of our n-PN/p-LP@aero-μGel to serve as a clinically promising platform,providing significant advancements for improved treatment of many respiratory diseases including IFP.