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.