Cocrystal@protein-anchoring nanococktail for combinatorially treating multidrug-resistant cancer

Multidrug resistance(MDR),the major mechanism by which various cancers develop specific resistance to therapeutic agents,has set up enormous obstacles to many forms of tumor chemotherapy.Traditional cocktail therapy administration,based on the combination of multiple drugs for anti-MDR chemotherapy,often suffers from inconsistent in vivo pharmacokinetic behaviors that cannot act synchronously on the lesions,leading to limited pharmacodynamic outcomes.Despite the emergence of nanomedicines,which has improved chemotherapeutic drugs’bioavailability and therapeutic effect on clinical application,these monotherapy-based nano-formulations still show poor progression in overcoming MDR.Herein,a“one stone and three birds”nanococktail integrated by a cocrystal@protein-anchoring strategy was purposed for triple-payload delivery,which paclitaxel-disulfiram cocrystal-like nanorods(NRs)were anchored with the basic protein drug Cytochrome c(Cyt C),followed by hyaluronic-acid modification.In particular,NRs were utilized as carrier-like particles to synchronously deliver biomacromolecule Cyt C into tumor cells and then promote cell apoptosis.Of note,on A549/Taxol drug-resistant tumor-bearing mice,the system with extraordinarily high encapsulation efficiency demonstrated prolonged in vivo circulation and increased tumor-targeting accumulation,significantly reversing tumor drug resistance and improving therapeutic efficacy.Our mechanistic study indicated that the system induced the apoptosis of Taxol-resistant tumor cells through the signal axis P-glycoprotein/Cyt C/caspase 3.Collectively,this nanococktail strategy offers a promising approach to improve the sensitivity of tumor cells to chemotherapeutic drugs and strengthen intractable drug-resistant oncotherapy.

Current research trends of nanomedicines

Owing to the inherent shortcomings of traditional therapeutic drugs in terms of inadequate therapeutic efficacy and toxicity in clinical treatment,nanomedicine designs have received widespread attention with significantly improved efficacy and reduced non-target side effects.Nanomedicines hold tremendous theranostic potential for treating,monitoring,diagnosing,and controlling various diseases and are attracting an unfathomable amount of input of research resources.Against the backdrop of an exponentially growing number of publications,it is imperative to help the audience get a panorama image of the research activities in the field of nanomedicines.Herein,this review elaborates on the development trends of nanomedicines,emerging nanocarriers,in vivo fate and safety of nanomedicines,and their extensive applications.Moreover,the potential challenges and the obstacles hindering the clinical translation of nanomedicines are also discussed.The elaboration on various aspects of the research trends of nanomedicines may help enlighten the readers and set the route for future endeavors.

Reactive oxygen species(ROS)-responsive size-reducible nanoassemblies for deeper atherosclerotic plaque penetration and enhanced macrophage-targeted drug delivery

Nanoparticle-based therapeutics represent potential strategies for treating atherosclerosis;however,the complex plaque microenvironment poses a barrier for nanoparticles to target the dysfunctional cells.Here,we report reactive oxygen species(ROS)-responsive and size-reducible nanoassemblies,formed by multivalent host-guest interactions betweenβ-cyclodextrins(β-CD)-anchored discoidal recombinant high-density lipoprotein(NP^(3)_(ST))and hyaluronic acid-ferrocene(HA-Fc)conjugates.The HA-Fc/NP^(3)_(ST)nanoassemblies have extended blood circulation time,specifically accumulate in atherosclerotic plaque mediated by the HA receptors CD44 highly expressed in injured endothelium,rapidly disassemble in response to excess ROS in the intimal and release smaller NP^(3)_(ST),allowing for further plaque penetration,macrophage-targeted cholesterol efflux and drug delivery.In vivo pharmacodynamicses in atherosclerotic mice shows that HA-Fc/NP^(3)_(ST)reduces plaque size by 53%,plaque lipid deposition by 63%,plaque macrophage content by 62%and local inflammatory factor level by 64%compared to the saline group.Meanwhile,HA-Fc/NP^(3)_(ST)alleviates systemic inflammation characterized by reduced serum inflammatory factor levels.Collectively,HA-Fc/NP^(3)_(ST)nanoassemblies with ROS-responsive and size-reducible properties exhibit a deeper penetration in atherosclerotic plaque and enhanced macrophage targeting ability,thus exerting effective cholesterol efflux and drug delivery for atherosclerosis therapy.