PEG Shell Research Articles

Sustained and Bioresponsive Two-Stage Delivery of Therapeutic miRNA via Polyplex Micelle-Loaded Injectable Hydrogels for Inhibition of Intervertebral Disc Fibrosis.

Intervertebral disc degeneration (IDD) is frequently caused by gradual pathological changes inside intervertebral discs (IVDs) and progressive fibrosis. MicroRNA-29 (miR-29) family possesses potent fibrosis suppression capability, but their application for treatment of chronic IDD is limited due to lack of suitable local delivery systems. In this report, given various overexpressed matrix metalloproteinases (MMPs) during IDD, injectable MMP-degradable hydrogels encapsulating MMP-responsive polyplex micelles are developed for sustained and bioresponsive delivery of miR-29a into nucleus pulposus cells via a two-stage process. Cationic block copolymers are designed to complex miR-29a, and subsequently mixed with the poly(ethylene glycol) (PEG) gelation precursors and MMP-cleavable peptide cross-linkers for in situ formation of polyplex micelle-encapsulated hydrogels in the diseased IVDs. In the presence of MMPs, the polyplex micelles are first released by MMP cleavage of the hydrogels, and subsequently, MMPs-responsive detachment of PEG shells from polyplex micelles contributes to efficient cellular uptake and endosomal escape. MiR-29a is demonstrated to effectively silence the expression of MMP-2, inhibit the fibrosis process, and reverse IDD in animal models through blocking the β-catenin translocation pathway from the cytoplasm to the nucleus. This two-stage bioresponsive local miRNA delivery system represents a novel and promising strategy for the treatment of chronic IDD.

Nitrilotriacetic Acid-Functionalized Glucose-Responsive Complex Micelles for the Efficient Encapsulation and Self-Regulated Release of Insulin.

Insulin plays a significant role in diabetes treatment. Although a huge number of insulin-loaded, glucose-responsive nanocarriers have been developed in past decades, most of them showed a lower loading capacity and efficiency due to the weak interaction between insulin and nanocarriers. In this work, a novel insulin-encapsulated glucose-responsive polymeric complex micelle (CM) is devised, showing (i) enhanced insulin-loading efficiency owing to the zinc ions' chelation by nitrilotriacetic acid (NTA) groups of NTA-functioned glycopolymer and the histidine imidazole of insulin, (ii) the glucose-triggered pulse release of insulin, and (iii) long stability under physiological conditions. This CM was fabricated by the self-assembly of block copolymer PEG- b-P(Asp- co-AspPBA) and glycopolymer P(Asp- co-AspGA- co-AspNTA), resulting in complex micelles with a PEG shell and a cross-linked core composed of phenylboronic acid (PBA)/glucose complexations. Notably, the modified nitrilotriacetic acid (NTA) groups of CM could specifically bind insulin via chelated zinc ions, thus enhancing the loading efficacy of insulin compared to that of nonmodified CM. The dynamic PBA/glucose complexation core of CM dissociates under the trigger of high glucose concentration (>2 g/L) while being quite stable in low glucose concentrations (<2 g/L), as demonstrated by the pulse release of insulin in vitro. Finally, in a murine model of type 1 diabetes, NTA-modified complex micelles loading an insulin (NTA-CM-INS) group exhibited a long hypoglycemic effect which is superior to that of free insulin in the PBS (PBS-INS) group and insulin-loaded complex micelles without an NTA modification (CM-INS) group. This long-term effect benefited from Zn(II) chelation by NTA-modified complex micelles and could avoid hypoglycemia caused by the burst release of insulin. Taken together, this constitutes a highly effective way to encapsulate insulin and release insulin via an on-demand manner for blood glucose control in diabetes.

Pressure-Stimulated Supercrystal Formation in Nanoparticle Suspensions.

Nanoparticles can self-organize into "supercrystals" with many potential applications. Different paths can lead to nanoparticle self-organization into such periodic arrangements. An essential step is the transition from an amorphous state to the crystalline one. We investigate how pressure can induce a phase transition of a nanoparticle model system in water from the disordered liquid state to highly ordered supercrystals. We observe reversible pressure-induced supercrystal formation in concentrated solutions of gold nanoparticles by means of small-angle X-ray scattering. The supercrystal formation occurs only at high salt concentrations in the aqueous solution. The pressure dependence of the structural parameters of the resulting crystal lattices is determined. The observed transition can be reasoned with the combined effect of salt and pressure on the solubility of the organic PEG shell that passivates the nanoparticles.

Engineered polyester-PEG nanoparticles prepared through a “grafting through” strategy and post-functionalization via Michael type addition

Free radical polymerization (FRP) is widely used in industrial processes as an efficient and versatile method to engineer polymeric nanoparticles (PNPs) of controlled size, narrowly distributed, and of well-defined surface properties. Functional Poly(ε-caprolactone) (PCL) and poly(lactic acid) (PLA) can be utilized as macromonomers in FRP in combination with a co-polymerizable poly(ethylene glycol) (PEG), to achieve aqueous dispersions of PNPs composed of a hydrophobic polyester core and a hydrophilic PEG shell of tuneable size. For several industrial and biological applications, PNPs also need surface functionalization to provide specific physicochemical characteristics, including stimuli-responsiveness, and bioactivity.In this work, a flexible “grafting through” strategy based on Ring opening polymerization (ROP) and FRP was proposed to obtain engineered polyester-PEG nanoparticles functionalized with acrylate groups on the hydrophilic shell. The presence of acrylates allows a versatile surface functionalization through Michael-type addition with a thiolated ligand (peptide), in aqueous solution under physiological pH, with the advantage of high conversion and absence of reaction side products. A cysteine-containing cyclic RGD was used as model peptide for conjugation, due to its potential application as ligand for endothelial cells. Results indicated that active cell targeting can be achieved by using this surface functionalization approach.

Shell of amphiphilic molecular bottlebrush matters as unimolecular micelle

Molecular bottlebrushes (MBBs) with a hydrophobic core and a hydrophilic shell may exist as well-defined unimolecular nanoparticles in water. However, they may also aggregate to form large particles if the structure of the hydrophilic and hydrophobic segments fail to be rationally controlled. Herein, a series of core-shell amphiphilic MBBs with a poly (ε-caprolactone) (PCL) backbone bearing two block copolymer side chains, poly (butyl acrylate)-b-poly ((oligo (ethylene glycol) acrylate) (PBA-b-POEGA) and poly (butyl acrylate)-b-poly (ethylene glycol) (PBA-b-PEG), were synthesized through grafting-from and grafting-onto strategies. Their hydrophilic shells are different in topology: POEGA is comblike whereas PEG is linear. The stability of the two kinds of MBB with the similar composition as unimolecular nanoparticles in water and their encapsulation capacity for guest-molecule were evaluated. Compared to the MBB with a linear PEG shell, those with comblike POEGA side chains remained stable against aggregation as demonstrated by atomic force microscopy and dynamic light scattering measurement. The MBB with a POEGA shell also displayed a much higher encapsulating capacity to a model guest molecule, pyrene, by hydrophobic interaction. This study provides guidance to the rational preparation of MBBs for applications as molecular vehicles.

Synthesis of a carbon dioxide-based amphiphilic block copolymer and its evaluation as a nanodrug carrier

A series of novel amphiphilic block copolymers poly(propylene carbonate)-block-mono-methoxy poly(ethylene oxide) (PPC-b-MPEG) composed of hydrophobic PPC segments and various lengths of hydrophilic MPEG segments was synthesized via “Click Chemistry” between azido-terminated PPC and alkynyl-terminated MPEG. The structure of the copolymers was characterized by FTIR, 1H NMR and 13C NHR techniques. Chlorpyrifos (CHP) was encapsulated within micelles through diffusion dialysis method, leading to the formation of CHP-loaded PPC-b-MPEG micelles. The resulting micelles were characterized further by dynamic light scattering (DLS) and scanning electron microscope. The results indicated that PPC-b-MPEG could self-assemble into nanosized micelles with PPC cores and PEG shells in aqueous solution. And the size, zeta potential, morphology, critical micelle concentration of PPC-b-MPEG micelles can be altered by changing the lengths of the PEG segments. CHP was encapsulated into PPC-b-MPEG2k micelles with loading capacity of 9.02% and entrapment efficiency of 77.28%. These results suggested that PPC-b-MPEG micelles would be a potential carrier for controlled release.

Anticoagulant Properties of Poly(sodium 2-(acrylamido)-2-methylpropanesulfonate)-Based Di- and Triblock Polymers.

Di- and triblock copolymers with low dispersity of molecular weight were synthesized using radical addition-fragmentation chain transfer polymerization. The copolymers contained anionic poly(sodium 2-acrylamido-2-methylpropanesulfonate) (PAMPS) block as an anticoagulant component. The block added to lower the toxicity was either poly(ethylene glycol) (PEG) or poly(2-(methacryloyloxy)ethyl phosphorylcholine) (PMPC). The polymers prolonged clotting times both in vitro and in vivo. The influence of the polymer architecture and composition on the efficacy of anticoagulation and safety parameters was evaluated. The polymer with the optimal safety/efficacy profile was PEG47- b-PAMPS108, i.e., a block copolymer with the degrees of polymerization of PEG and PAMPS blocks equal to 47 and 108, respectively. The anticoagulant action of copolymers is probably mediated by antithrombin, but it differs from that of unfractionated heparin. PEG47- b-PAMPS108 also inhibited platelet aggregation in vitro and increased the prostacyclin production but had no antiplatelet properties in vivo. PEG47- b-PAMPS108 anticoagulant activity can be efficiently reversed with a copolymer of PEG and poly((3-(methacryloylamino)propyl)trimethylammonium chloride) (PMAPTAC) (PEG41- b-PMAPTAC53, HBC), which may be attributed to the formation of polyelectrolyte complexes with PEG shells without anticoagulant properties.

Effects of the multilayer structures on Exenatide release and bioactivity in microsphere/thermosensitive hydrogel system.

Traditional polypeptide-loaded PLGA microspheres (PM) using emulsion electrospray techniques often exhibit unsteady release and limited bioactivity. To solve these two problems, an Exenatide (EXT)-loaded multilayer system composed ofPM and thermosensitive hydrogel was prepared by the emulsion electrospray technique in this study. Hydrogel mixture were loaded in PLGA microspheres as Depot-hydrogel to prepare Gel/PM. The PM/Gel and Gel/PM/Gel systems were obtained by dispersion of PM and Gel/PM into hydrogel mixture, respectively. EXT in Gel/PM/Gel showed a constantly in vitro release for 30 days, which was significantly enhanced in comparison of those in the PM/Gel and the Gel/PM. PM/Gel and Gel/PM/Gel showed diminished burst release and no platform period compared with PM and Gel/PM. And these could be because the introduced Matrix-hydrogel outside, as a buffer layer, inhibited burst releases and exhibited a sustained manner. The inner Depot-hydrogelstructure slowed the PLGA degradation rate and drug release rate. As well, more than 15-day blood glucose levels in KKAy mice were greatly maintained at 7.50-9.50 mmol/L after a single subcutaneous injection of Gel/PM/Gel (4.95 μg/kg). Spatial stability and further bioactivity of released EXT were well protected by EXT-hydrogel complexes, and undesirable uptake of EXT and microspheres via phagocytes were also decreased by PEG shell. Thus, the long-acting microspheres/hydrogel multilayer system prepared by emulsion electrospray technique showed promising potentials for loading hydrophilic polypeptides and proteins.

PH-Responsive Nanoscale Covalent Organic Polymers as a Biodegradable Drug Carrier for Combined Photodynamic Chemotherapy of Cancer.

Covalent organic polymers (COPs) are a promising class of cross-linked polymeric networks and porous structures composed of covalent organic molecules that attract extensive attention. Despite increasing interest in applying COPs for applications in nanomedicine, the pH-sensitive COPs that are able to sensitively respond to the slightly acidic tumor microenvironment for tumor-specific drug delivery and therapy remain to be explored to our best knowledge. Herein, a new style of pH-responsive COPs were prepared using acryloyl meso-tetra( p-hydroxyphenyl) porphine (acryloyl-THPP) to react with 4,4'-trimethylene dipiperidine to form the pH-responsive cross-linked biodegradable β-amino esters (BAEs). Amine-modified poly(ethylene glycol) (PEG) was then introduced to terminate the reaction and form the PEG shell. The formulated pH-responsive THPP-BAE-PEG COPs can be utilized to encapsulate anticancer drug doxorubicin (DOX) due to their porous structure. Upon intravenous injection, such DOX-loaded COPs show a prolonged blood circulation as well as an efficient tumor accumulation. Along with the pH-triggered drug release for chemotherapy, the singlet oxygen produced by THPP under light exposure for photodynamic therapy would further endow us a combined treatment strategy, which offers synergistic antitumor effects in our in vivo tumor model experiments. Our study illustrates that COPs fabricated with tumor microenvironment responsive linkers may be a promising type of materials for applications in cancer nanomedicine.

Insights into the Mechanism of Bile Salt Aggregates Forming in a PEGylated Amphiphilic Polymer/Bile Salt Mixed Micelle

AbstractTailoring the structure of core‐shell interface of amphiphilic copolymer micelles provides a potential to mediate the drug release from micelles. Here, bile salts were used to alter the molecular geometry of core‐shell structured amphiphilic copolymer micelles. With the different sodium deoxycholate (NaDC) addtions in the methoxy polyethylene glycol‐poly(D,L‐lactic acid) (MPEG‐PDLLA) solutions, the NaDC molecule could form different deoxycholic acid (DCA) dimers in the core and shell of micelles. A face‐to‐face DCA dimer structure could form and insert into the core of micelles when a small NaDC addition. This dimer could accelerate the drug release. At a high NaDC addition, a new back‐to‐back DCA dimer could form in the PEG shell region that would reduce the rate of drug release. The results obtained provide fundamental insights into the role of bile salts in adjusting the drug release of amphiphilic copolymer micelles and demonstrate the future potential for controlled drug‐delivery applications.

Poly(Ethylene Glycol)-Polylactide Micelles for Cancer Therapy.

For the treatment of malignancy, many therapeutic agents, including small molecules, photosensitizers, immunomodulators, proteins and genes, and so forth, have been loaded into nanocarriers for controllable cancer therapy. Among these nanocarriers, polymeric micelles have been considered as one of the most promising nanocarriers, some of which have already been applied in different stages of clinical trials. The successful advantages of polymeric micelles from bench to bedside are due to their special core/shell structures, which can carry specific drugs in certain disease conditions. Particularly, poly(ethylene glycol)–polylactide (PEG–PLA) micelles have been considered as one of the most promising platforms for drug delivery. The PEG shell effectively prevents the adsorption of proteins and phagocytes, thereby evidently extending the blood circulation period. Meanwhile, the hydrophobic PLA core can effectively encapsulate many therapeutic agents. This review summarizes recent advances in PEG–PLA micelles for the treatment of malignancy. In addition, future perspectives for the development of PEG–PLA micelles as drug delivery systems are also presented.

Cancer-specific pro-oxidant therapy using low-toxic polypeptide micelles encapsulating piperlongumine

Pro-oxidant therapy utilizing pro-oxidant drugs that can induce cytotoxic oxidative stress in cancer cells has attracted widespread attention for cancer-specific therapy. Piperlongumine (PL) has gained great interest as a novel pro-oxidant agent because it can exhibit cancer-specific cytotoxicity via elevation of intracellular reactive oxygen species (ROS) in cancer cells. However, its therapeutic efficacy has been limited by its poor water-solubility, which necessitates developing suitable drug carriers for PL delivery. In this study, low-toxic poly(ethylene glycol)-poly(histidine) [PEG-poly(His)] copolymer was developed for effective intracellular delivery of PL. Stable micelles composed of a PEG shell and a poly(His) core encapsulating PL were prepared. In vitro study revealed that plain PEG-poly(His) micelles without PL were low-toxic. Importantly, PL-PEG-poly(His) micelles showed superior cytotoxicity in cancer cells over normal cells due to the PL-induced, dramatic increase of intracellular ROS in cancer cells in comparison with normal cells. PL-PEG-poly(His) micelles were further modified with folic acid (FA) to enhance their cancer-specific pro-oxidant therapy. As compared to FA-free micelles, FA-PL-PEG-poly(His) micelles revealed more facilitated cellular uptake and anticancer efficacy in folate receptor-positive cancer cells. This study demonstrates that PL-PEG-poly(His) micelles are efficient and low-toxic carriers for PL delivery, thus leading to effective and cancer-targeted pro-oxidant therapy.

Controlled Self-assembly of Thermo-responsive Amphiphilic H-shaped Polymer for Adjustable Drug Release

Despite the fact that some progress has been made in the self-assembly of H-shaped polymers, the corresponding self-assemblies that respond to external stimulus and are further utilized to adjust the release of drugs are still deficient. The stimuli-responsive segments with amphiphilic H-shaped structure are generally expected to enhance the controllability of self-assembly process. The synthesis and self-assembly behavior of thermo-responsive amphiphilic H-shaped polymers with poly(ethylene glycol) (PEG), polytetrahydrofuran (PTHF) and poly(N-isopropyl acrylamide) (PNIPAM) as building blocks are reported in this paper. The inner architecture structure and size of complex micelles formed by H-shaped self-assemblies were effectively adjusted when the solution temperature was increased above the lower critical solution temperature of PNIPAM segments. Furthermore, it was found that the architecture of self-assemblies underwent a transition from the complex micelles based on primary micelles with hybrid PEG/PNIPAM shells to large complex micelles based on primary micelles with hybrid PTHF/PNIPAM cores and PEG shells during the thermal-induced self-assembly process. The adjustable release rate of doxorubicin (DOX) from the DOX-loaded complex micelles and basic cell experiments further proved the feasibility of these self-assemblies as the thermal-responsive drug delivery system.

Reconfigurable Peptide Nanotherapeutics at Tumor Microenvironmental pH.

Peptide nanomaterials have recently attracted considerable interest in the biomedical field. However, their poor bioavailability and less powerful therapeutic efficacy hamper their further applications. Herein, we discovered reconfigurable and activated nanotherapeutics in the tumor microenvironment. Two peptides, that is, a pH-responsive peptide HLAH and a matrix metalloprotease-2 (MMP2)-sensitive peptide with a poly(ethylene glycol) (PEG) terminal were conjugated onto the hydrophobic poly(β-thioester)s backbones to gain the copolymer P-S-H. The therapeutic activity of the HLAH peptide could be activated in tumors owing to its reconfiguration under microenvironmental pH. The resultant copolymers self-assembled into nanoparticles under physiological condition, with HLAH in cores protected by PEG shells. The moderate size (∼100 nm) and negative potential enabled the stable circulation of P-S-H in the bloodstream. Once arrived at the tumor site, the P-S-H nanoparticles were stimulated by overexpressed MMP2 and acidic pH, and subsequently the shedding of the PEG shell and protonation of the HLAH peptide induced the reassembly of nanoparticles, resulting in the formation of nanoparticles with activated cytotoxic peptides on the surface. In vivo experiments demonstrated that the reorganized nanoassembly contained three merits: (1) effective accumulation in the tumor site, (2) enhanced antitumor capacity, and (3) no obvious toxic effect at the treatment dose. This on-site reorganization strategy provides an avenue for developing high-performance peptide nanomaterials in cancer treatment.

PH-Responsive Poly(Ethylene Glycol)-block-Polylactide Micelles for Tumor-Targeted Drug Delivery.

A biodegradable micellar drug delivery system with a pH-responsive sheddable PEG shell was developed using an acetal-linked poly(ethylene glycol)-block-polylactide (PEG-a-PLA) copolymer and applied to the tumoral release of paclitaxel (PTX). The micelles with a diameter of ∼100 nm were stable in PBS at pH 7.4, started shedding the shell and aggregating slowly at pH 6.5, and decomposed faster at pH 5.5. PTX-loaded micelles (M-PTX) with a drug loading of 6.9 wt % exhibited pH-triggered PTX release in simulated tumoral acidic environments corresponding to the extracellular and intracellular spaces. In vitro experiments showed that the micelles were noncytotoxic to different cell lines, while M-PTX inhibited the proliferation and promoted the apoptosis of Hela cells. An in vivo study with Hela tumor-bearing mice indicated that M-PTX efficiently inhibited tumor growth. Because of these properties, the PEG-a-PLA micellar system appears to have bright prospects as a tumor-targeting drug carrier.

Photoresponsive biodegradable poly(carbonate)s with pendento‐nitrobenzyl ester

ABSTRACTPhotoresponsive amphiphilic diblock poly(carbonate)s mPEG113‐b‐PMNCnwith pendento‐nitrobenzyl ester group were synthesized through ring‐opening polymerization (ROP) using 1,8‐diazabi‐cyclo[5.4.0]undec‐7‐ene (DBU) as catalyst and monomethoxy poly(ethylene glycol) (mPEG) as macroinitiator. In aqueous solution, the copolymers can self‐assemble to spherical micelles with a PC core and a PEG shell. The critical micelle concentration (CMC), size, and morphology of the micelles were demonstrated by means of fluorescence spectroscopy, transmission electron microscopes (TEM), and dynamic light scattering (DLS). Under UV light irradiation, the amphiphilic copolymer micelles disassembled because of the photocleavage ofo‐NB ester, and the light‐controlled release behaviors of payload Nile red were further proved. This study provides a convenient way to construct smart poly(carbonate)s nanocarriers for controlled drug release. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem.2017,55, 2770–2780

Effect of Alkylation on the Cellular Uptake of Polyethylene Glycol-Coated Gold Nanoparticles.

Alkyl groups (CnH2n+1) are prevalent in engineered bionanomaterials used for many intracellular applications, yet how alkyl groups dictate the interactions between nanoparticles and mammalian cells remains incomprehensively investigated. In this work, we report the effect of alkylation on the cellular uptake of densely polyethylene glycol-coated nanoparticles, which are characterized by their limited entry into mammalian cells. Specifically, we prepare densely PEGylated gold nanoparticles that bear alkyl chains of varying carbon chain lengths (n) and loading densities (termed "alkyl-PEG-AuNPs"), followed by investigating their uptake by Kera-308 keratinocytes. Strikingly, provided a modest alkyl mass percentage of 0.2% (2 orders of magnitude lower than that of conventional lipid-based NPs) in their PEG shells, dodecyl-PEG-AuNPs (n = 12) and octadecyl-PEG-AuNPs (n = 18) can enter Kera-308 cells 30-fold more than methoxy-PEG-AuNPs (no alkyl groups) and hexyl-PEG-AuNPs (n = 6) after 24 h of incubation. Such strong dependence on n is valid for all serum concentrations considered (even under serum-free conditions), although enhanced serum levels can trigger the agglomeration of alkyl-PEG-AuNPs (without permanent aggregation of the AuNP cores) and can attenuate their cellular uptake. Additionally, alkyl-PEG-AuNPs can rapidly enter Kera-308 cells via the filipodia-mediated pathway, engaging the tips of membrane protrusions and accumulating within interdigital folds. Most alkyl-PEG-AuNPs adopt the "endo-lysosomal" route of trafficking, but ∼15% of them accumulate in the cytosol. Regardless of intracellular location, alkyl-PEG-AuNPs predominantly appear as individual entities after 24 h of incubation. Our work offers insights into the incorporation of alkyl groups for designing bionanomaterials for cellular uptake and cytosolic accumulation with intracellular stability.

Redox-Sensitive Stomatocyte Nanomotors: Destruction and Drug Release in the Presence of Glutathione.

The development of artificial nanomotor systems that are stimuli‐responsive is still posing many challenges. Herein, we demonstrate the self‐assembly of a redox‐responsive stomatocyte nanomotor system, which can be used for triggered drug release under biological reducing conditions. The redox sensitivity was introduced by incorporating a disulfide bridge between the hydrophilic poly(ethylene glycol) block and the hydrophobic polystyrene block. When incubated with the endogenous reducing agent glutathione at a concentration comparable to that within cells, the external PEG shells of these stimuli‐responsive nanomotors are cleaved. The specific bowl‐shaped stomatocytes aggregate after the treatment with glutathione, leading to the loss of motion and triggered drug release. These novel redox‐responsive nanomotors can not only be used for remote transport but also for drug delivery, which is promising for future biomedical applications.

Redox‐Sensitive Stomatocyte Nanomotors: Destruction and Drug Release in the Presence of Glutathione

AbstractThe development of artificial nanomotor systems that are stimuli‐responsive is still posing many challenges. Herein, we demonstrate the self‐assembly of a redox‐responsive stomatocyte nanomotor system, which can be used for triggered drug release under biological reducing conditions. The redox sensitivity was introduced by incorporating a disulfide bridge between the hydrophilic poly(ethylene glycol) block and the hydrophobic polystyrene block. When incubated with the endogenous reducing agent glutathione at a concentration comparable to that within cells, the external PEG shells of these stimuli‐responsive nanomotors are cleaved. The specific bowl‐shaped stomatocytes aggregate after the treatment with glutathione, leading to the loss of motion and triggered drug release. These novel redox‐responsive nanomotors can not only be used for remote transport but also for drug delivery, which is promising for future biomedical applications.

Smart Asymmetric Vesicles with Triggered Availability of Inner Cell-Penetrating Shells for Specific Intracellular Drug Delivery.

Smart nanocarriers attract considerable interest in the filed of precision nanomedicine. Dynamic control of the interaction between nanocarriers and cells offers the feasibility that in situ activates cellular internalization at the targeting sites. Herein, we demonstrate a novel class of enzyme-responsive asymmetric polymeric vesicles self-assembled from matrix metalloproteinase (MMP)-cleavable peptide-linked triblock copolymer, poly(ethylene glycol)-GPLGVRG-b-poly(ε-caprolactone)-b-poly(3-guanidinopropyl methacrylamide) (PEG-GPLGVRG-PCL-PGPMA), in which the cell-penetrating PGPMA segments asymmetrically distribute in the outer and inner shells with fractions of 9% and 91%, respectively. Upon treatment with MMP-2 to cleave the stealthy PEG shell, the vesicles undergo morphological transformation into fused multicavity vesicles and small nanoparticles, accompanied by redistribution of PGPMA segments with 76% exposed to the outside. The vesicles after dePEGylation show significantly increased cellular internalization efficiency (∼10 times) as compared to the original ones due to the triggered availability of cell-penetrating shells. The vesicles loading hydrophobic anticancer drug paclitaxel (PTX) in the membrane exhibit significantly enhanced cytotoxicity against MMP-overexpressing HT1080 cells and multicellular spheroids. The proposed vesicular system can serve as a smart nanoplatform for in situ activating intracellular drug delivery in MMP-enriched tumors.