Tumor microenvironment-responsive self-assembly of barium titanate nanoparticles with enhanced piezoelectric catalysis capabilities for efficient tumor therapy

Catalytic therapy based on piezoelectric nanoparticles has become one of the effective strategies to eliminate tumors.However,it is still a challenge to improve the tumor delivery efficiency of piezoelectric nanoparticles,so that they can penetrate normal tissues while specifically aggregating at tumor sites and subsequently generating large amounts of reactive oxygen species(ROS)to achieve precise and efficient tumor clearance.In the present study,we successfully fabricated tumor microenvironment-responsive assembled barium titanate nanoparticles(tma-BTO NPs):in the neutral pH environment of normal tissues,tma-BTO NPs were monodisperse and possessed the ability to cross the intercellular space;whereas,the acidic environment of the tumor triggered the self-assembly of tma-BTO NPs to form submicron-scale aggregates,and deposited in the tumor microenvironment.The self-assembled tma-BTO NPs not only caused mechanical damage to tumor cells;more interestingly,they also exhibited enhanced piezoelectric catalytic efficiency and produced more ROS than monodisperse nanoparticles under ultrasonic excitation,attributed to the mutual extrusion of neighboring particles within the confined space of the assembly.tma-BTO NPs exhibited differential cytotoxicity against tumor cells and normal cells,and the stronger piezoelectric catalysis and mechanical damage induced by the assemblies resulted in significant apoptosis of mouse breast cancer cells(4T1);while there was little damage to mouse embryo osteoblast precursor cells(MC3T3-E1)under the same treatment conditions.Animal experiments confirmed that peritumoral injection of tma-BTO NPs combined with ultrasound therapy can effectively inhibit tumor progression non-invasively.The tumor microenvironment-responsive self-assembly strategy opens up new perspectives for future precise piezoelectric-catalyzed tumor therapy.

Functionally Oriented Tumor Microenvironment Responsive Polymeric Nanoassembly:Engineering and Applications

The excellent drug encapsulation,prolonged in vivo circulation time,enhanced pharmacokinetics,and reduced adverse effects make the polymeric assemblies ideal carriers in nanomedicine,and become an emerging research field with rapid development.In vivo,the polymer nanoassemblies will experience five steps,including circulation in the blood,accumulation in the tumoral site,penetration into the deep tumor tissue to reach cancer cells,internalization into cancer cells,and intracellular drug release.However,although tremendous efforts have been made to the material design,currently available carriers still have difficulties in fulfilling all of the requirements.Moreover,the long-standing dilemma of the synchronized stability and permeability of vesicles is still a big challenge,which confused researchers for a long time.This feature article tbcuses on the recent progress of single-or multi-stimuli triggered theranostic platforms,and the extracellularly reengineered shell-sheddable polymeric nanocarriers are systematically discussed.The perspectives for future developments in the nanocarriers functioned with artificial helical polymers(the potential cell-penetrating peptides mimics)are also proposed.We speculate that this feature article can fit the interesting of diverse readers and a guideline for the design of next generation of drug nanocarriers.

Bioresponsive micro-to-nano albumin-based systems for targeted drug delivery against complex fungal infections

As a typical human pathogenic fungus,Cryptococcus neoformans is a life-threatening invasive fungal pathogen with a worldwide distribution causing w700,000 deaths annually.Cryptococcosis is not just an infection with multi-organ involvement,intracellular survival and extracellular multiplication of the fungus also play important roles in the pathogenesis of C.neoformans infections.Because adequate accumulation of drugs at target organs and cells is still difficult to achieve,an effective delivery strategy is desperately required to treat these infections.Here,we report a bioresponsive micro-to-nano(MTN)system that effectively clears the C.neoformans in vivo.This strategy is based on our in-depth study of the overexpression of matrix metalloproteinase 3(MMP-3)in infectious microenvironments(IMEs)and secreted protein acidic and rich in cysteine(SPARC)in several associated target cells.In this MTN system,bovine serum albumin(BSA,a natural ligand of SPARC)was used for the preparation of nanoparticles(NPs),and then microspheres were constructed by conjugation with a special linker,which mainly consisted of a BSA-binding peptide and an MMP-3-responsive peptide.This MTN system was mechanically captured by the smallest capillaries of the lungs after intravenous injection,and then hydrolyzed into BSA NPs by MMP-3 in the IMEs.The NPs further targeted the lung tissue,brain and infected macrophages based on the overexpression of SPARC,reaching multiple targets and achieving efficient treatment.We have developed a size-tunable strategy where microspheres"shrink"to NPs in IMEs,which effectively combines active and passive targeting and may be especially powerful in the fight against complex fungal infections.

Intelligent bio-assembly imaging-guided platform for real-time bacteria sterilizing and infectious therapy

Bacterial infection is rising as a threatening health issue.Because of the present delay in early diagnosis of bacterial diseases as well as the abuse of antibiotics,it has become a vital issue in the development of in-time detection and therapy of bacterial infections.Herein,we designed a multifunctional nanotheranostics platform based on the unique micro-environment of bacterial infections to achieve specific bioimaging and simultaneous inactivation of the target bacteria.We showed that in bacterial infections,the metal precursors(i.e.,HAuCl_(4),FeCl_(2),and herring sperm DNA)could be readily bio-self-assembled to multifunctional nanoclusters(NCs)that exhibit luminescence,in which AuCl_(4)-was biosynthesized via reductive biomolecules such as NADPH to the fluorescent AuNCs.The DNA may assist as an encapsulation and delivery vector,and Fe^(2+)served as a fluorescence intensifier and reduced reactive oxygen species(ROS)to produce the iron oxides.While the bacteria were being visualized,the microenvironment-responsive NCs were enabled to sterilize bacteria efficiently due to electrostatic effect,cell membrane destruction,inhibition of biofilm formation,and ROS accumulation.Besides,the bio-responsive self-assembled NCs complexes contributed to accelerating bacteria-infected wound healing and showed negligible side effects in long-term toxicity tests in vivo.Also,intracellular molecules involved in microenvironmental response were investigated.The work may become an effective strategy for the detection and real-time sterilization of intractable bacterial infections.