Dual-targeting AAV9P1-mediated neuronal reprogramming in a mouse model of traumatic brain injury

Traumatic brain injury results in neuronal loss and glial scar formation.Replenishing neurons and eliminating the consequences of glial scar formation are essential for treating traumatic brain injury.Neuronal reprogramming is a promising strategy to convert glial scars to neural tissue.However,previous studies have reported inconsistent results.In this study,an AAV9P1 vector incorporating an astrocyte-targeting P1 peptide and glial fibrillary acidic protein promoter was used to achieve dual-targeting of astrocytes and the glial scar while minimizing off-target effects.The results demonstrate that AAV9P1 provides high selectivity of astrocytes and reactive astrocytes.Moreover,neuronal reprogramming was induced by downregulating the polypyrimidine tract-binding protein 1 gene via systemic administration of AAV9P1 in a mouse model of traumatic brain injury.In summary,this approach provides an improved gene delivery vehicle to study neuronal programming and evidence of its applications for traumatic brain injury.

Carrier-free highly drug-loaded biomimetic nanosuspensions encapsulated by cancer cell membrane based on homology and active targeting for the treatment of glioma

Nanosuspensions,as a new drug delivery system for insoluble drugs,are only composed of a drug and a small amount of stabilizer,which is dispersed in an aqueous solution with high drug-loading,small particle size,high dispersion,and large specific surface area.It can significantly improve the dissolution,bioavailability,and efficacy of insoluble drugs.In this study,paclitaxel nanosuspensions((PTX)NS)were prepared by an ultrasonic precipitation method,with the characteristics of simple preparation and easy repetition.With the help of a homologous targeting mechanism,a kind of glioma C6 cancer cell membrane(CCM)-coated(PTX)NS was developed and modified with DWSW peptide to obtain DWSW-CCM-(PTX)NS with the functions of BBB penetration and tumor targeting.The results showed that the cancer cell membrane could effectively camouflage the nanosuspensions so that it was not cleared by the immune system and could cross the blood-brain-barrier(BBB)and selectively target tumor tissues.Cell uptake experiments and in vivo imaging confirmed that the uptake of DWSW-CCM-(PTX)NS by tumor cells and the distribution in intracranial gliomas increased.Cytotoxicity test and in vivo anti-glioma studies showed that DWSW-CCM-(PTX)NS could significantly inhibit the growth of glioma cells and significantly prolong the survival time of glioma-bearing mice.Finally,the cancer cell membrane coating endowed the nanosuspensions with the biological properties of homologous adhesion and immune escape.This study provides an integrated solution for improving the targeting of nanosuspensions and demonstrates the encouraging potential of biomimetic nanosuspensions applicable to tumor therapy.

Macrophage membrane-coated nanocarriers Co-Modified by RVG29 and TPP improve brain neuronal mitochondria-targeting and therapeutic efficacy in Alzheimer's disease mice

Neuronal mitochondrial dysfunction caused by excessive reactive oxygen species(ROS)is an early event of sporadic Alzheimer's disease(AD),and considered to be a key pathologic factor in the progression of AD.The targeted delivery of the antioxidants to mitochondria of injured neurons in brain is a promising therapeutic strategy for AD.A safe and effective drug delivery system(DDS)which is able to cross the blood-brain barrier(BBB)and target neuronal mitochondria is necessary.Recently,bioactive materials-based DDS has been widely investigated for the treatment of AD.Herein,we developed macrophage(MA)membrane-coated solid lipid nanoparticles(SLNs)by attaching rabies virus glycoprotein(RVG29)and triphenylphosphine cation(TPP)molecules to the surface of MA membrane(RVG/TPP-MASLNs)for functional antioxidant delivery to neuronal mitochondria.According to the results,MA membranes camouflaged the SLNs from being eliminated by RESrich organs by inheriting the immunological characteristics of macrophages.The unique properties of the DDS after decoration with RVG29 on the surface was demonstrated by the ability to cross the BBB and the selective targeting to neurons.After entering the neurons in CNS,TPP further lead the DDS to mitochondria driven by electric charge.The Genistein(GS)-encapsulated DDS(RVG/TPP-MASLNs-GS)exhibited the most favorable effects on reliveing AD symptoms in vitro and in vivo by the synergies gained from the combination of MA membranes,RVG29 and TPP.These results demonstrated a promising therapeutic candidate for delaying the progression of AD via neuronal mitochondria-targeted delivery by the designed biomimetic nanosystems.

UM15 reinforces a lymphocyte-mimicking nanotrap for precise HIV-1 inhibition

Even the potential of T cell-mimicking nanotrap for long term viral control due to its overcoming of human immunodeficiency virus(HIV)genetic diversity and viral resistance,the robust HIV inhibition was not expected because these nanotraps displayed no obvious advantages compared with the infinite host cells.Herein,a glycoprotein 120(gp120)-targeting polypeptide UM15 reinforced lymphocyte-mimicking nanotrap was constructed,and its improved HIV-1 inhibiting efficacy was validated.According to the results,the constructed nanotraps exhibited evident escaping ability from uptake of the mononuclear phagocyte system and highly improved binding ability with gp120 proteins.The constructed nanotraps neutralized all tested HIV-1 pseudo typed viruses with IC80 of 21.0μg/mL,and inhibited both X4-tropic and R5-tropic HIV-1 with IC80 of 34.4 and 20.6μg/mL,respectively.Approximately 40%of gp120 was observed to be shed from pseudo virus,and above 40%bystander T cells were prevented from gp120-induced death by the constructed nanotraps.The safety of the constructed nanotraps was confirmed both in vitro and in mice.Therefore,the constructed nanotraps could specifically neutralize free HIV-1,selectively bind with gp120 expressing HIV-1 infected cells,cause gp120 shedding,inhibit gp120-induced bystander T cell killing on the premise of safety,and were considered as promising therapeutic agents for precise inhibition of HIV.

Cell relay-delivery improves targeting and therapeutic efficacy in tumors

Cell-mediated drug delivery system(CDDS)has shown great potential for cancer therapy.However,a single cell-mediated drug delivery mechanism has not generally been successful,particularly for systemic administration.To augment the antitumor therapy efficacy,herein,we propose a strategy of cell relay-delivery for the use of artificially damaging/aging erythrocytes to hitchhike on circulating monocytes/macrophages for intratumoral accumulation of anticancer drugs.This biomimetic relay-delivery strategy was derived from the manner in which circulating monocytes/macrophages in body specifically engulf damaged/senescent erythrocytes and actively transmigrate into the tumor bulk.The strategy elegantly combines the natural functions of both cells,which therefore provides a new perspective to challenge current obstacles in drug delivery.According to the strategy,we developed biotinylated erythrocyte-poly(lactic-co-glycolic acid)(PLGA)nanoparticle hybrid DDSs(bE-NPs)using avidin-biotin coupling.In such a system,biotinylated erythrocytes can mimic the natural property of damaged/senescent erythrocytes,while PLGA NPs are capable of encapsulating anticancer drugs and promoting sustained drug release.Anticancer drugs can effectively target tumor sites by two steps.First,by using biotinylated erythrocytes as the carrier,the drug-loaded PLGA NPs could be specifically phagocytized by monocytes/macrophages.Second,by taking advantage of the tumor-tropic property of monocytes/macrophages,the drug-loaded PLGA NPs could be efficiently transported into the tumor bulk.After encapsulating vincristine(VIN)as the model drug,bE-NPs exhibited the most favorable antitumor effects in vitro and in vivo by the cell relay-delivery effect.These results demonstrate that the cell relay-delivery provides a potential method for improving tumor treatment efficacy.

Corrigendum to“Macrophage membrane-coated nanocarriers Co-Modified by RVG29 and TPP improve brain neuronal mitochondria-targeting and therapeutic efficacy in Alzheimer’s disease mice”[Bioactive materials 6(2021)529-542]

The authors regret publishing the incorrect address and affiliation.They have been now revised as follows:1.The Addresses are updated from.“a School of Traditional Chinese Medicine,Shenyang Pharmaceutical University,Shenyang,110016,PR China b State Key Laboratory of Toxicology and Medical Countermeasures,Beijing Institute of Pharmacology and Toxicology,Beijing,100850,PR China c School of Functional Food and Wine,Shenyang Pharmaceutical University,Shenyang,10016,PR China.