Drug delivery under cover of erythrocytes extends drug half-life: A thrombolytic targeting therapy utilizing microenvironment-responsive artificial polysaccharide microvesicles.

The development of thrombolytic drug carriers capable of thrombus-targeting, prolonged circulation time, intelligent responsive release, and the ability to inhibit thrombotic recurrences remains a promising but significant challenge. To tackle this, an artificial polysaccharide microvesicle drug delivery system (uPA-CS/HS@RGD-ODE) was constructed. It is composed of cationic chitosan and anionic heparin assembled in a layer by layer structure, followed by surface modification using RGD peptide and 2-(N-oxide-N,N-diethylamino) ethylmethacrylate (ODE) before encapsulation of urokinase-type plasminogen activator (uPA). The effect of chitosan on the basic performances of uPA-CS/HS@RGD-ODE was estimated. The in vitro results suggest the uPA carrier, CS/HS@RGD-ODE, displayed outstanding targeting specific to activated platelets (61 %) and microenvironment-responsiveness at pH 6.5, facilitating thrombus-targeting and a controlled drug release, respectively. Most importantly, in vivo experiment suggests ODE from uPA-CS/HS@RGD-ODE substantially extends the half-life of uPA (120 min), as uPA-CS/HS@RGD-ODE can adhere onto erythrocytes and deliver uPA under cover of erythrocytes enabling a prolonged circulation time in the bloodstream. Further tail vein and abdominal aorta thrombosis models confirmed uPA-CS/HS@RGD-ODE exhibited superior targeting and thrombolysis capabilities compared to systemic administration of free uPA. To the knowledge of authors, this may be the first study to develop new drug carriers for delivery of thrombolytic drugs under the cover of erythrocytes for extended drug half-lives.

Bacteria-induced aggregation of bioorthogonal gold nanoparticles for SERS imaging and enhanced photothermal ablation of Gram-positive bacteria.

The challenge in antimicrobial photothermal therapy (PTT) is to develop strategies for decreasing the damage to cells and increasing the antibacterial efficiency. Herein, we report a novel theranostic strategy based on bacteria-induced gold nanoparticle (GNP) aggregation, in which GNPs in situ aggregated on the bacterial surface via specific targeting of vancomycin and bioorthogonal cycloaddition. Plasmonic coupling between adjacent GNPs exhibited a strong "hot spot" effect, enabling effective surface enhanced Raman scattering (SERS) imaging of bacterial pathogens. More importantly, in situ aggregation of GNPs showed strong NIR adsorption and high photothermal conversion, allowing enhanced photokilling activity against Gram-positive bacteria. In the absence of bacterial strains, GNPs were dispersed and showed a very low photothermal effect, minimizing the side effects towards surrounding healthy tissues. Given the above advantages, the bioorthogonal theranostic strategy developed in this study may find potential applications in treating bacterial infection and even multidrug-resistant bacteria.