Hyaluronidase with pH‐responsive Dextran Modification as an Adjuvant Nanomedicine for Enhanced Photodynamic‐Immunotherapy of Cancer

The condensed tumor extracellular matrix (ECM) consisting of cross‐linked hyaluronic acid (HA) is one of key factors that results in the aberrant tumor microenvironment (TME) and the resistance to various types of therapies. Herein, hyaluronidase (HAase) is modified by a biocompatible polymer, dextran (DEX), via a pH‐responsive traceless linker. The formulated DEX‐HAase nanoparticles show enhanced enzyme stability, reduced immunogenicity, and prolonged blood half‐life after intravenous injection. With efficient tumor passive accumulation, DEX‐HAase within the acidic TME would be dissociated to release native HAase, which afterward triggers the breakdown of HA to loosen the ECM structure, subsequently leading to enhanced penetration of oxygen and other therapeutic agents. The largely relieved tumor hypoxia would promote the therapeutic effect of nanoparticle‐based photodynamic therapy (PDT), accompanied by the reverse of the immunosuppressive TME to boost cancer immunotherapy. Interestingly, the therapeutic responses achieved by the combination of PDT and anti‐programmed death‐ligand 1 (anti‐PD‐L1) checkpoint blockade therapy could be significantly enhanced by pretreatment with DEX‐HAase. In addition to destructing tumors with direct light exposure, a robust abscopal effect is achieved after such treatment, which is promising for tumor metastasis inhibition. The work presents a new type of adjuvant nanomedicine to assist photodynamic‐immunotherapy of cancer, by effective modulation of TME.     

Gel–Liposome‐Mediated Co‐Delivery of Anticancer Membrane‐Associated Proteins and Small‐Molecule Drugs for Enhanced Therapeutic Efficacy

A programmed drug‐delivery system that can transport different anticancer therapeutics to their distinct targets holds vast promise for cancer treatment. Herein, a core–shell‐based “nanodepot” consisting of a liposomal core and a crosslinked‐gel shell (designated Gelipo) is developed for the sequential and site‐specific delivery (SSSD) of tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) and doxorubicin (Dox). As a small‐molecule drug intercalating the nuclear DNA, Dox is loaded in the aqueous core of the liposome, while TRAIL, acting on the death receptor (DR) on the plasma membrane, is encapsulated in the outer shell made of crosslinked hyaluronic acid (HA). The degradation of the HA shell by HAase that is concentrated in the tumor environment results in the rapid extracellular release of TRAIL and subsequent internalization of the liposomes. The parallel activity of TRAIL and Dox show synergistic anticancer efficacy. The half‐maximal inhibitory concentration (IC₅₀) of TRAIL and Dox co‐loaded Gelipo (TRAIL/Dox‐Gelipo) toward human breast cancer (MDA‐MB‐231) cells is 83 ng mL^–1 (Dox concentration), which presents a 5.9‐fold increase in the cytotoxicity compared to 569 ng mL^–1 of Dox‐loaded Gelipo (Dox‐Gelipo). Moreover, with the programmed choreography, Gelipo significantly improves the inhibition of the tumor growth in the MDA‐MB‐231 xenograft tumor animal model.     

Effective and Selective Anti‐Cancer Protein Delivery via All‐Functions‐in‐One Nanocarriers Coupled with Visible Light‐Responsive,Reversible Protein Engineering

Efficient intracellular delivery of protein drugs and tumor‐specific activation of protein functions are critical toward anti‐cancer protein therapy. However, an omnipotent protein delivery system that can harmonize the complicated systemic barriers as well as spatiotemporally manipulate protein function is lacking. Herein, an “all‐functions‐in‐one” nanocarrier doped with photosensitizer (PS) is developed and coupled with reactive oxygen species (ROS)‐responsive, reversible protein engineering to realize cancer‐targeted protein delivery, and spatiotemporal manipulation of protein activities using long‐wavelength visible light (635 nm) at low power density (5 mW cm^?2). Particularly, RNase A is caged with H₂O₂‐cleavable phenylboronic acid to form 4‐nitrophenyl 4‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)benzyl carbonate (NBC)‐modified RNase (RNBC), which is encapsulated in acid‐degradable, ketal‐crosslinked PEI (KPEI)‐based nanocomplexes (NCs) coated with PS‐modified hyaluronic acid (HA). Such NCs harmonize the critical processes for protein delivery, wherein HA coating renders NCs with long blood circulation and cancer cell targeting, and KPEI enables endosomal escape as well as acid‐triggered intracellular RNBC release. Tumor‐specific light irradiation generates H₂O₂ to kill cancer cells and restore the protein activity, thus achieving synergistic anti‐cancer efficacy. It is the first time to photomanipulate protein functions by coupling ROS‐cleavable protein caging with PS‐mediated ROS generation, and the “all‐functions‐in‐one” nanocarrier represents a promising example for the programmed anti‐cancer protein delivery.     

Redox Sensitive Hyaluronic Acid‐Decorated Graphene Oxide for Photothermally Controlled Tumor‐Cytoplasm‐Selective Rapid Drug Delivery

Nanocarriers capable of circumventing various biological barriers between the site of administration and the therapeutic target hold great potential for cancer treatment. Herein, a redox‐sensitive, hyaluronic acid‐decorated graphene oxide nanosheet (HSG) is developed for tumor cytoplasm‐specific rapid delivery using near‐infrared (NIR) irradiation controlled endo/lysosome disruption and redox‐triggered cytoplasmic drug release. Hyaluronic acid (HA) modification through redox‐sensitive linkages permits HSG a range of advantages over the standard graphene oxide, including high biological stability, enhanced drug‐loading capacity for aromatic molecules, HA receptor‐mediated active tumor targeting, greater NIR absorption and thermal energy translation, and a sharp redox‐dependent response for accelerated cargo release. Results of in vivo and in vitro testing indicate a high loading of doxorubicin (DOX) onto HSG. Selective delivery to HA‐receptor overexpressing tumors is achieved through passive and active targeting with minimized unfavorable interactions with blood components. Cytoplasm‐specific DOX delivery is then achieved through NIR controlled endo/lysosome disruption along with redox‐triggered release of DOX in glutathione rich areas. HSG's specificity is resulted in enhanced cytotoxicity of chemotherapeutics with minimal collateral damage to healthy tissues in a xenograft animal tumor model. HSG is validated the programmed delivery of therapeutic agents in a spatiotemporally controlled manner to overcome multiple biological barriers results in specific and enhanced cancer treatment.     

Biodegradable Nanoparticles of Polyacrylic Acid–Stabilized Amorphous CaCO3 for Tunable pH‐Responsive Drug Delivery and Enhanced Tumor Inhibition

Inorganic nanoparticles (NPs) are promising drug delivery carriers owing to their high drug loading efficiency, scalable preparation, facile functionalization, and chemical/thermal stability. However, the clinical translation of inorganic nanocarriers is often hindered by their poor biodegradability and lack of controlled pH response. Herein, a fully degradable and pH‐responsive DOX@ACC/PAA NP (pH 7.4–5.6) is developed by encapsulating doxorubicin (DOX) in poly(acrylic acid) (PAA) stabilized amorphous calcium carbonate (ACC) NPs. The DOX‐loaded NPs have small sizes (62 ± 10 nm), good serum stability, high drug encapsulation efficiency (>80%), and loading capacity (>9%). By doping proper amounts of Sr²⁺ or Mg²⁺, the drug release of NPs can be further modulated to higher pH responsive ranges (pH 7.7–6.0), which enables drug delivery to the specific cell domains of tissues with a less acidic microenvironment. Tumor inhibition and lower drug acute toxicity are further confirmed via intracellular uptake tests and zebrafish models, and the particles also improve pharmacokinetics and drug accumulation in mouse xenograft tumors, leading to enhanced suppression of tumor growth. Owing to the excellent biocompatibility, biodegradability, and tunable drug release behavior, the present hybrid nanocarrier may find broad applications in tumor therapy.     

High‐Drug‐Loading Mesoporous Silica Nanorods with Reduced Toxicity for Precise Cancer Therapy against Nasopharyngeal Carcinoma

Nanorod‐based drug delivery systems have attracted great interest because of their enhanced cell internalization capacity and improved drug loading property. Herein, novel mesoporous silica nanorods (MSNRs) with different lengths are synthesized and used as nanocarriers to achieve higher drug loading and anticancer activity. As expected, MSNRs‐based drug delivery systems can effectively enhance the loading capacity of drugs and penetrate into tumor cells more rapidly than spherical nanoparticles due to their greater surface area and trans‐membrane transporting rates. Interestingly, these tailored MSNRs also enhance the cellular uptake of doxorubicin (DOX) in cancer cells, thus significantly enhancing its anticancer efficacy for hundreds of times by inducing of cell apoptosis. Internalized MSNRs‐DOX triggers intracellular reactive oxygen species (ROS) overproduction, which subsequently activates p53 and mitogen‐activated protein kinases (MAPKs) pathways to promote cell apoptosis. MSNRs‐DOX nanosystem also shows prolonged blood circulation time in vivo. In addition, MSNRs‐DOX significantly inhibits in vivo tumor growth in nude mice model and effectively reduced its in vivo toxicity. Therefore, this study provides an effective and safe strategy for designing chemotherapeutic agents for precise cancer therapy.     

Tumor‐Microenvironment‐Activated In Situ Self‐Assembly of Sequentially Responsive Biopolymer for Targeted Photodynamic Therapy

A sequentially responsive photosensitizer‐integrated biopolymer is developed for tumor‐specific photodynamic therapy, which is capable of forming long‐retained aggregates in situ inside tumor tissues. Specifically, the photosensitizer zinc phthalocyanine (ZnPc) is conjugated with polyethylene glycol (PEG) via pH‐labile maleic acid amide linker and then immobilized onto the hyaluronic acid (HA) chain using a redox‐cleavable disulfide linker. The PEG segment can enhance blood circulation of the molecular carrier after intravenous administration and be shed after reaching the acidic tumor microenvironment, allowing the remaining fragment to self‐assemble into large clusters in situ to avoid backward diffusion and improve tumor retention. This process is driven by hydrophobic interactions and does not require additional external actuation. The aggregates are then internalized by the tumor cells via HA‐facilitated endocytosis, and the high glutathione level in tumor cells eventually leads to the intracellular release of ZnPc to facilitate its interaction with the subcellular lipid structures. This tumor‐triggered morphology‐based delivery platform is constructed with clinically tested components and could potentially be applied to other hydrophobic therapeutics.     

Self‐Adaptive Antibacterial Porous Implants with Sustainable Responses for Infected Bone Defect Therapy

The development of responsive antibacterial implants is highly significant for the treatment of implant‐associated infection. In this study, one self‐adaptive antibacterial porous implant with sustainable responses is flexibly designed and constructed for infected bone defect therapy. Porous hydroxyapatite (HA) implants derived from nature bones, one typical implant, are first functionalized via low‐cytotoxic ethanediamine‐functionalized poly(glycidyl methacrylate) brushes, and gentamicin sulfate (GS, a kind of aminoglycoside antibiotic in clinic) is subsequently conjugated by an acid‐responsive bond to produce smart antibacterial HA implants (HA–GS). The release of GS can be triggered by the acidic environment induced by the metabolism of bacteria for self‐adaptive antibacterial response. Due to the good drug loading capacity and chemical stability of HA–GS in neutral condition, the sustainable antibacterial ability is readily achieved for long‐term applications. The highly effective in vivo anti‐infection therapy with HA–GS is demonstrated in one infected bone defect rabbit model. The implant‐associated infection is completely inhibited by HA–GS at the early stage and the defected bones exhibit superior recovery at the late stage. This design strategy of sustainable self‐adaptive antibacterial implants will provide a promising concept for the prevention and therapy of implant‐associated infections.     

pH‐Responsive Peptide Mimic Shell Cross‐Linked Magnetic Nanocarriers for Combination Therapy

The design and development of water dispersible, pH responsive peptide mimic shell cross‐linked magnetic nanocarriers (PMNCs) using a facile soft‐chemical approach is reported. These nanocarriers have an average size about 10 nm, are resistant to protein adsorption in physiological medium, and transform from a negatively charged to a positively charged form in the acidic environment. The terminal amino acid on the shell of the magnetic nanocarriers allows us to create functionalized exteriors with high densities of organic moieties (both amine and carboxyl) for conjugation of drug molecules. The drug‐loading efficiency of the nanocarriers is investigated using doxorubicin hydrochloride (DOX) as a model drug to evaluate their potential as a carrier system. Results show high loading affinity of nanocarriers for anticancer drug, their sustained release profile, magnetic‐field‐induced heating, and substantial cellular internalization. Moreover, the enhanced toxicity to tumor cells by DOX‐loaded PMNCs (DOX‐PMNCs) under an AC magntic field suggest their potential for combination therapy involving hyperthermia and chemotherapy.     

Dual‐Stage‐Light‐Guided Tumor Inhibition by Mitochondria‐Targeted Photodynamic Therapy

In this paper, a self‐delivery system PpIX‐PEG‐(KLAKLAK)₂ (designated as PPK) is fabricated to realize mitochondria‐targeted photodynamic tumor therapy. It is found that the PPK self‐delivery system exhibited high drug loading efficacy as well as novel capacity in generation of intracellular reactive oxygen species (ROS). This study also indicated that the photochemical internalization effect of the photosensitizer protoporphyrin IX (PpIX) under a short time light irradiation improved the cellular internalization of PPK. On the contrary, PPK could target to the subcellular organelle mitochondria due to the presence of proapoptosis (KLAKLAK)₂ peptide. Importantly, the in situ generation of ROS in mitochondria enhanced the photodynamic therapy efficacy under another long time irradiation, leading to significant cell death with decreased mitochondrial membrane potential. Besides, relative high tumor accumulation, minimal systemic cytotoxicity and efficacious long‐term tumor inhibition in vivo are also confirmed by using a murine model. All these results demonstrated the self‐delivery system PPK with a dual‐stage light irradiation strategy is a promising nanoplatform for tumor treatment.     

Light‐Inducible Exosome‐Based Vehicle for Endogenous RNA Loading and Delivery to Leukemia Cells

Exosomes are a novel and promising drug delivery platform because of their endogenous origin, stability, biocompatibility, and other unique features. As the efficient loading and delivery of long RNA to target cells for therapeutic purposes remains challenging, a new exosome‐based RNA delivery system is proposed using a controllable RNA enrichment and releasing protocol. The system employs RNA aptamer–protein interactions and reversible light‐inducible protein–protein interaction modules by remolding exosome producer cells. Endogenous microRNA 21 (miR‐21) sponges, inhibitors of miR‐21, are successfully enriched on the plasma membrane and are sorted into exosomes by the biogenesis of the exosomes. The loading capacity of miR‐21 sponges is enhanced by 14‐fold in the light‐inducible loading system. In addition, targeted delivery of miR‐21 to leukemia cells is achieved by modifying exosomes with the cholesterol‐conjugated aptamer AS1411, resulting in significant cell apoptosis by blocking the function of miR‐21 in leukemia cells. This work provides an exosome‐based light‐inducible vehicle to efficiently load and deliver long endogenous RNA, which can enable more RNA‐based therapeutics for personalized cancer medicine.     

Water‐Soluble Poly(N‐isopropylacrylamide)–Graphene Sheets Synthesized via Click Chemistry for Drug Delivery

Covalently functionalized graphene sheets are prepared by grafting a well‐defined thermo‐responsive poly(N‐isopropylacrylamide) (PNIPAM) via click chemistry. The PNIPAM‐grafted graphene sheets (PNIPAM‐GS) consist of about 50% polymer, which endows the sheets with a good solubility and stability in physiological solutions. The PNIPAM‐GS exhibits a hydrophilic to hydrophobic phase transition at 33 °C, which is relatively lower than that of a PNIPAM homopolymer because of the interaction between graphene sheets and grafted PNIPAM. Moreover, through π–π stacking and hydrophobic interaction between PNIPAM‐GS and an aromatic drug, the PNIPAM‐GS is able to load a water‐insoluble anticancer drug, camptothecin (CPT), with a superior loading capacity of 15.6 wt‐% (0.185 g CPT per g PNIPAM‐GS). The in vitro drug release behavior of the PNIPAM‐GS‐CPT complex is examined both in water and PBS at 37 °C. More importantly, the PNIPAM‐GS does not exhibit a practical toxicity and the PNIPAM‐GS‐CPT complex shows a high potency of killing cancer cells in vitro. The PNIPAM‐GS is demonstrated to be an effective vehicle for anticancer drug delivery.     

Assemblies of Peptide‐Cytotoxin Conjugates for Tumor‐Homing Chemotherapy

Peptide‐drug conjugates are prodrugs that have the advantages of precise molecular structure and the direct exploitation of tumor‐homing, penetration or the cellular uptake abilities of the peptides such as the neuropilin‐1 receptor targeting peptide. The prodrugs generally have fast blood clearance due to their low molecular weights and thus are made to self‐assemble into nanostructures, preferably nanosized micelles and vesicles for intravenous administration, to slow their renal clearance. However, most peptidyl prodrugs usually form precipitates, irregular nanofibers or gels that are unsuitable for intravenous injection. Herein, a arginine‐glycine‐aspartic acid‐lysine (RGDK) peptide and cytotoxin 7‐ethyl‐10‐hydroxycamptothecin (SN38) are used to synthesize the tumor‐homing prodrugs (SN38‐Peps) and explore their structure–micelle formation relationships. A small library of SN38‐Peps is obtained using different structures of peptides, linkers, and drug conjugation sites, and the factors affecting the assembly of SN38‐Peps as well as the stability of formed micelles are investigated. An optimized SN38‐Pep, (MOM)SN38(20)‐CRGDK, is finally obtained which forms stable micelles with a hydrodynamic diameter around 110 nm and a fixed drug loading content as high as 35%. The micelles show a prolonged blood circulation, significantly enhanced tumor accumulation, and therefore improved anticancer activity as compared to the non‐targeting prodrug and a clinically used anticancer drug.     

Plant‐Based Hollow Microcapsules for Oral Delivery Applications: Toward Optimized Loading and Controlled Release

Efficient oral administration of protein‐based therapeutics faces significant challenges due to degradation from the highly acidic conditions present in the stomach and proteases present in the digestive tract. Herein, investigations into spike‐covered sunflower sporopollenin exine capsules (SECs) for oral protein delivery using bovine serum albumin (BSA) as a model drug are reported and provide significant insights into the optimization of SEC extraction, SEC loading, and controlled release. The phosphoric‐acid‐based SEC extraction process is optimized. Compound loading is shown to be driven by the evacuation of air bubbles from SEC cavities through the porous SEC shell wall, and vacuum loading is shown to be the optimal loading method. Three initial BSA‐loading proportions are evaluated, leading to a practical loading efficiency of 22.3 ± 1.5 wt% and the determination that the theoretical maximum loading is 46.4 ± 2.5 wt%. Finally, an oral delivery formulation for targeted intestinal delivery is developed by tableting BSA‐loaded SECs and enteric coating. BSA release is inhibited for 2 h in simulated gastric conditions followed by 100% release within 8 h in simulated intestinal conditions. Collectively, these results indicate that sunflower SECs provide a versatile platform for the oral delivery of therapeutics.     

Structure‐Invertible Nanoparticles for Triggered Co‐Delivery of Nucleic Acids and Hydrophobic Drugs for Combination Cancer Therapy

Here, a new type of structure‐invertible, redox‐responsive polymeric nanoparticle for the efficient co‐delivery of nucleic acids and hydrophobic drugs in vitro and in vivo is reported for the first time, to combat the major challenges facing combination cancer therapy. The co‐delivery vector, which is prepared by conjugating branched poly(ethylene glycol) with dendrimers of two generations (G2) through disulfide linkages, is able to complex nucleic acids and load hydrophobic drugs with high loading capacity through structure inversion. The cleavage of disulfide linkages at intracellular glutathione‐rich reduction environment significantly decreases the cytotoxicity, and promotes more efficient drug release and gene transfection in vitro and in vivo. The co‐delivery carrier also displays enhanced endosomal escape capability and improved serum stability in vitro as compared with G2, and exhibits prolonged residence time and stronger transfection activity in vivo. Most importantly, co‐delivery of doxorubicin (DOX) and B‐cell lymphoma 2 (Bcl‐2) small interfering RNA (siRNA) exerts a combinational effect against tumor growth in murine tumor models in vivo, which is much more effective than either DOX or Bcl‐2 siRNA‐based monotherapy. The structure‐invertible nanoparticles may constitute a promising stimuli‐responsive system for the efficacious co‐delivery of multiple cargoes in future clinical applications of combination cancer therapies.     

A Multi‐Gradient Targeting Drug Delivery System Based on RGD‐l‐TRAIL‐Labeled Magnetic Microbubbles for Cancer Theranostics

The accurately and efficiently targeted delivery of therapeutic/diagnostic agents into tumor areas in a controllable fashion remains a big challenge. Here, a novel cancer targeting magnetic microbubble is elaborately fabricated. First, the γ‐Fe₂O₃ magnetic iron oxide nanoparticles are optimized to chemically conjugate on the surface of polymer microbubbles. Then, arginine‐glycine‐aspartic acid‐l ‐tumor necrosis factor‐related apoptosis‐inducing ligand (RGD‐l ‐TRAIL), antitumor targeting fusion protein, is precisely conjugated with magnetic nanoparticles of microbubbles to construct RGD molecularly targeted magnetic microbubble, which is defined as RGD‐l ‐TRAIL@MMBs. Such RGD‐l ‐TRAIL@MMBs is endowed with the multigradient cascade targeting ability following by magnetic targeting, RGD, as well as enhanced permeability and retention effect regulated targeting to result in high cancerous tissue targeting efficiency. Due to the highly specific accumulation of RGD‐l ‐TRAIL@MMBs in the tumor, the accurate diagnostic information of tumor can be obtained by dual ultrasound and magnetic resonance imaging. After imaging, the TRAIL molecules as anticancer agent also get right into the cancer cells by nanoparticle‐ and RGD‐mediated endocytosis to effectively induce the tumor cell apoptosis. Therefore, RGD‐l ‐TRAIL conjugated magnetic microbubbles could be developed as a molecularly targeted multimodality imaging delivery system with the addition of chemotherapeutic cargoes to improve cancer diagnosis and therapy.     

A Versatile Prodrug Strategy to In Situ Encapsulate Drugs in MOF Nanocarriers: A Case of Cytarabine‐IR820 Prodrug Encapsulated ZIF‐8 toward Chemo‐Photothermal Therapy

Zeolitic imidazolate framework‐8 (ZIF‐8) is an attractive metal organic framework (MOF) in drug delivery. Strong interaction between drugs and ZIF‐8 is essential for high drug loadings through in situ construction of MOFs. However, only limited drugs with unique functional groups (? COOH, ? SO₃H, et al.) can interact with ZIF‐8 and be encapsulated satisfactorily so far. Drugs without these functional groups are difficult to be loaded due to the lack of strong interaction. Herein a versatile prodrug strategy is proposed to solve the problems encountered by MOFs. Cytarabine (Ara) is chosen as a model drug since it cannot be loaded in ZIF‐8 satisfactorily by itself. New indocyanine green (IR820) is utilized to bond with Ara for the formation of prodrug (Ara‐IR820) and endows the prodrug with fluorescence imaging‐guided chemo‐photothermal therapy, in which sulfonic groups strengthen the interaction between prodrug and ZIF‐8. This prodrug loaded ZIF‐8 is further functionalized with hyaluronic acid (HA) to result in active‐targeting HA/Ara‐IR820@ZIF‐8 nanoparticles. The in vitro and in vivo results demonstrate its excellent visual cancer therapy with tumor‐targeted and pH‐responsive release behavior. This design offers a new concept to solve the drug loading problem of MOFs, exhibiting a flexible strategy to expand the biomedical applications of MOFs.     

Functionalized‐Silk‐Based Active Optofluidic Devices

Silk protein from the silkworm Bombyx mori has excellent chemical and mechanical stability, biocompatibility, and optical properties. Additionally, when the protein is purified and reformed into materials, the biochemical functions of dopants entrained in the protein matrix are stabilized and retained. This unique combination of properties make silk a useful multifunctional material platform for the development of sensor devices. An approach to increase the functions of silk‐based devices through chemical modifications to demonstrate an active optofluidic device to sense pH is presented. Silk protein is chemically modified with 4‐aminobenzoic acid to add spectral‐color‐responsive pH sensitivity. The functionalized silk is combined with the elastomer poly(dimethyl siloxane) in a single microfluidic device. The microfluidic device allows spatial and temporal control of the delivery of analytic solutions to the system to provide the optical response of the optofluidic device. The modified silk is stable and spectrally responsive over a wide pH range from alkaline to acidic.     

Treatment of Malignant Brain Tumor by Tumor‐Triggered Programmed Wormlike Micelles with Precise Targeting and Deep Penetration

The efficient and specific drug delivery to brain tumor is a crucial challenge for successful systemic chemotherapy. To overcome these limitations, here a tumor‐triggered programmed wormlike micelle is reported with precise targeting and deep penetration to treat malignant gliomas, which is composed of pH‐responsive mPEG‐b‐PDPA copolymer and bioreducible cyclic RGD peptide targeted cytotoxic emtansine (DM1) conjugates (RGD‐DM1). The RGD‐DM1 loaded nanoscaled wormlike micelles (RNW) exhibit nanometer‐sized wormlike assemblies with the transverse diameter of 21.3±1.8 nm and length within 60–600 nm, and the RGD targeting peptide in RNW is 4.2% in weight. RNW can be dissociated at intracellular acidic environments to release RGD‐DM1, and be further degraded into DM1 by cleavage of disulfide bonds in the reductive milieu. In particular, by exploiting the unique wormlike structure and the RGD targeting peptide modification, RNW can be endowed with obviously enhanced drug delivery to brain, precise targeting to brain tumor, deep penetration into tumor mass, and efficient internalization into glioma cells in a programmed manner, thereby surprisingly leading to an 88.9% inhibition on tumor progression in an orthotopic brain tumor model. Therefore, the properly designed RNW can provide a promising delivery platform for systemic chemotherapy of brain tumor.     

Virus‐Inspired Mimics Based on Dendritic Lipopeptides for Efficient Tumor‐Specific Infection and Systemic Drug Delivery

Herein, multifunctional mimics of viral architectures and infections self‐assembled from tailor‐made dendritic lipopeptides for programmed targeted drug delivery are reported. These viral mimics not only have virus‐like components and nanostructures, but also possess virus‐like infections to solid tumor and tumor cells. Encouragingly, the viral mimics provide the following distinguished features for tumor‐specific systemic delivery: i) stealthy surface to resist protein interactions and prolong circulation time in blood, ii) well‐defined nanostructure for passive targeting to solid tumor site, iii) charge‐tunable shielding for tumor extracellular pH targeting, iv) receptor‐mediated targeting to enhance tumor‐specific uptake, and v) supramolecular lysine‐rich architectures mimicking viral subcellular targeting for efficient endosomal escape and nuclear delivery. This bioinspired design make in vivo tumor suppression by drug‐loaded viral mimics against BALB/c mice bearing 4T1 tumor greatly exceed the positive control group (more than three times). More importantly, viral mimics hold great potentials to reduce side effects and decrease tumor metastasis after systemic administration.