A Bio‐Inspired Rod‐Shaped Nanoplatform for Strongly Infecting Tumor Cells and Enhancing the Delivery Efficiency of Anticancer Drugs

The rapid clearance of circulating nanocarriers in blood during systemic drug delivery remains a challenging hurdle in cancer chemotherapy. Here, inspired by the unique features of bacterial pathogens, an original biodegradable polymer micellar system with a rod‐like shape similar to the morphology of bacterial pathogens is developed. These novel nanocarriers have excellent features such as a great capacity of overcoming the rapid clearance of reticuloendothelial system (RES) with long blood circulation, high cellular internalization, and enhanced therapeutic efficacy against cancers. In vivo pharmacokinetic studies in mice reveal that the rod‐like micelles of ≈40 nm in diameter and 600 nm in length possess a minimal uptake by the RES and excellent blood circulation half‐lives (t_1/2β = 24.23 ± 2.87 h) for carrying doxorubicin in contrast to spheres (t_1/2β = 8.39 ± 0.53 h). The antitumor activity of the rod‐shaped micelles in Balb/c mice bearing H22 tumor xenograft models reveals that they are promptly internalized by tumor cells, resulting in their superior potency and efficacy against artificial solid tumors. These findings suggest that the bio‐inspired nanocarriers as an emerging drug delivery platform may have considerable benefits for enhancing the delivery efficiency of anticancer drugs and in turn enhancing cancer therapy in future clinical applications.     

A Virus‐Mimicking pH‐Responsive Acetalated Dextran‐Based Membrane‐Active Polymeric Nanoparticle for Intracellular Delivery of Antitumor Therapeutics

Achieving cellular internalization and endosomal escape remains a major challenge for many antitumor therapeutics, especially macromolecular drugs. Viral drug carriers are reported for efficient intracellular delivery, but with limited choices of payloads. In this study, a novel polymeric nanoparticle (ADMAP) is developed, resembling the structure and functional features of a virus. ADMAP is synthesized by grafting endosomolytic poly(lauryl methacrylate‐co‐methacrylic acid) on acetalated dextran. The endosomolytic polymer mimics the capsid protein for endosomal escape, and acetalated dextran resembles the viral core for accommodating payloads. After polymer synthesis, the subsequent controlled nanoprecipitation on a microfluidic device yields uniform nanoparticles with high encapsulation efficiency. At late endosomal pH (5.0), the ADMAP particles successfully destabilize endosomal membranes and release the drug payloads synergistically, resulting in a greater therapeutic efficacy compared with that of free anticancer drugs. Further conjugation of a tumor‐penetrating peptide enhances the antitumor efficacy toward 3D spheroids and finally leads to spheroid disintegration. The unique structure along with the synergistic endosomal escape and drug release make ADMAP nanoparticles favorable for intracellular delivery of antitumor therapeutics.     

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.     

Steric Protected and Illumination‐Activated Tumor Targeting Accessory for Endowing Drug‐Delivery Systems with Tumor Selectivity

Here, an ABA‐typed polymer, octadecyl‐polyethylene glycol (biotin)‐(o‐nitrobenzyl)‐octadecyl ester (CPB‐p‐C) with an o‐nitrobenzyl group inserted between polyethylene glycol (PEG) and octadecyl ester is synthesized as an illumination‐activated tumor targeting accessory for micelle‐based drug carriers. The functional accessory can form a flower‐like structure with folded PEG segments in aqueous solution to hide targeting biotin ligands in the core of the mixed micelle. Thus the specific binding between biotin and avidin can be suppressed by the steric hindrance of PEG shell. Upon illumination, the flower‐like structure of CPB‐p‐C is destroyed due to the cleavage of the o‐nitrobenzyl group and the biotin moieties are exposed on the surface of the micelle through the stretching process of PEG segments, generating ligand‐receptor‐mediated targeted delivery. By confocal laser scanning microscopy and flow cytometry, the illumination‐activated, tumor‐targeting delivery is studied. The influence of the amount of functional accessory in the mixed micelle on the targeting property is investigated and the optimal amount of CPB‐p‐C to achieve less side effects and better illumination activated tumor targeting activity is identified. The observed properties of CPB‐p‐C qualify it as a promising functional accessory to endow traditional drug‐delivery systems with tumor selectivity.     

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.     

Uniform Virus‐Like Co–N–Cs Electrocatalyst Derived from Prussian Blue Analog for Stretchable Fiber‐Shaped Zn–Air Batteries

Zn‐air batteries (ZABs) offer promising commercialization perspectives for stretchable and wearable electronic devices as they are environment‐friendly and have high theoretical energy density. However, current devices suffer from limited energy efficiency and durability because of the sluggish oxygen reduction and evolution reactions kinetics in the air cathode as well as degenerative stretchability of solid‐state electrolytes under highly alkaline conditions. Herein, excellent bifunctional catalytic activity and cycling stability is achieved by using a newly developed Co–N–C nanomaterial with a uniform virus‐like structure, prepared via a facile carbonization of a prussian blue analogue (PBA). Furthermore, a solid‐state dual‐network sodium polyacrylate and cellulose (PANa‐cellulose) based hydrogel electrolyte is synthesized with good alkaline‐tolerant stretchability. A solid‐state fiber‐shaped ZAB fabricated using this hydrogel electrolyte, the virus‐like Co–N–Cs air cathode, and a zinc spring anode display excellent stretchability of up to 500% strain without damage, and outstanding electrochemical performance with 128 mW cm^?2 peak power density and good cycling stability for >600 cycles at 2 mA. The facile synthesis strategy demonstrated here opens up a new avenue for developing highly active PBA‐derived catalyst and shows, for the first time, that virus‐like structure can be favorable for electrochemical performance.     

IL4‐Receptor‐Targeted Dual Antitumoral Apoptotic Peptide—siRNA Conjugate Lipoplexes

Targeted delivery remains the major limitation in the development of small interfering RNA (siRNA) therapeutics. The successful siRNA multistep delivery requires precise carriers of substantial complexity. To achieve this, a monodisperse carrier is presented, synthesized by solid‐phase supported chemistry. The sequence‐defined assembly contains two oleic acids attached to a cationizable oligoaminoamide backbone in T‐shape configuration, and a terminal azide functionality for coupling to the atherosclerotic plaque‐specific peptide‐1 (AP‐1) as the cell targeting ligand for interleukin‐4 receptor (IL‐4R) which is overexpressed in a variety of solid cancers. For combined cytosolic delivery with siRNA, different apoptotic peptides (KLK, BAK, and BAD) are covalently conjugated via bioreversible disulfide linkage to the 5′‐end of the siRNA sense strand. siRNA‐KLK conjugates provide the highest antitumoral potency. The optimized targeted carrier is complexed with dual antitumoral siEG5‐KLK conjugates. The functionality of each subdomain is individually confirmed. The lipo‐oligomer confers stable assembly of siRNA conjugates into spherical 150–250 nm sized nanoparticles. Click‐shielding with dibenzocyclootyne‐PEG‐AP‐1 (DBCO‐PEG‐AP‐1) mediates an IL‐4R‐specific cell targeting and gene silencing in tumor cells. Most importantly, formulation of the siEG5‐KLK conjugate displays enhanced apoptotic tumor cell killing due to the combined effect of mitotic arrest by EG5 gene silencing and mitochondrial membrane disruption by KLK.     

Cancer Cell Membrane‐Coated Gold Nanocages with Hyperthermia‐Triggered Drug Release and Homotypic Target Inhibit Growth and Metastasis of Breast Cancer

The cell‐specific targeting drug delivery and controlled release of drug at the cancer cells are still the main challenges for anti‐breast cancer metastasis therapy. Herein, the authors first report a biomimetic drug delivery system composed of doxorubicin (DOX)‐loaded gold nanocages (AuNs) as the inner cores and 4T1 cancer cell membranes (CMVs) as the outer shells (coated surface of DOX‐incorporated AuNs (CDAuNs)). The CDAuNs, perfectly utilizing the natural cancer cell membranes with the homotypic targeting and hyperthermia‐responsive ability to cap the DAuNs with the photothermal property, can realize the selective targeting of the homotypic tumor cells, hyperthermia‐triggered drug release under the near‐infrared laser irradiation, and the combination of chemo/photothermal therapy. The CDAuNs exhibit a stimuli‐release of DOX under the hyperthermia and a high cell‐specific targeting of the 4T1 cells in vitro. Moreover, the excellent combinational therapy with about 98.9% and 98.5% inhibiting rates of the tumor volume and metastatic nodules is observed in the 4T1 orthotopic mammary tumor models. As a result, CDAuNs can be a promising nanodelivery system for the future therapy of breast cancer.     

Chitosan–Alginate Microcapsules Provide Gastric Protection and Intestinal Release of ICAM‐1‐Targeting Nanocarriers,Enabling GI Targeting In Vivo

When administered intravenously, active targeting of drug nanocarriers (NCs) improves biodistribution and endocytosis. Targeting may also improve NC oral delivery to treat gastrointestinal (GI) pathologies or for systemic absorption. However, GI instability of targeting moieties compromises this strategy. This study explores whether encapsulation of antibody‐coated NCs in microcapsules would protect against gastric degradation, providing NC release and targeting in intestinal conditions. Nanoparticles coated with antibodies against intercellular adhesion molecule‐1 (anti‐ICAM) or nonspecific immunoglobulin G (IgG) are encapsulated in chitosan (shell) ‐ alginate (core) microcapsules. Encapsulation efficiency is >95% and NC relase from microcapsules in storage is <10%. There is minimal NC release at gastric pH (<10%) and burst release at intestinal pH (75%–85%). Encapsulated NCs afford increased protection against degradation (threefold to fourfold) and increased cell targeting (8–20‐fold) after release versus the nonencapsulated NCs. Mouse oral gavage shows that microencapsulation provides 38%–65% greater protection of anti‐ICAM NCs in the GI tract, 40% lower gastric retention, and fourfold to ninefold enhanced intestinal biodistribution versus nonencapsulated NCs. Therefore, microencapsulation of antibody‐targeted NCs may enable active targeting strategies to be effective in the context of oral drug delivery.     

Tumor‐Microenvironment‐Adaptive Nanoparticles Codeliver Paclitaxel and siRNA to Inhibit Growth and Lung Metastasis of Breast Cancer

Prolonged circulation, specific and effective uptake by tumor cells, and rapid intracellular drug release are three main factors for the drug delivery systems to win the battle against metastatic breast cancer. In this work, a tumor microenvironment‐adaptive nanoparticle co‐loading paclitaxel (PTX) and the anti‐metastasis siRNA targeting Twist is prepared. The nanoparticle consists of a pH‐sensitive core, a cationic shell, and a matrix metalloproteinase (MMP)‐cleavable polyethylene glycol (PEG) corona conjugated via a peptide linker. PEG will be cut away by MMPs at the tumor site, which endows the nanoparticle with smaller particle size and higher positive charge, leading to more efficient cellular uptake in tumor cells and higher intra‐tumor accumulation of both PTX and siRNA in the 4T1 tumor‐bearing mice models compared to the nanoparticles with irremovable PEG. In addition, acid‐triggered drug release in endo/lysosomes is achieved through the pH‐sensitive core. As a result, the MMP/pH dual‐sensitive nanoparticles significantly inhibit tumor growth and pulmonary metastasis. Therefore, this tumor‐microenvironment‐adaptive nanoparticle can be a promising codelivery vector for effective therapy of metastatic breast cancer due to simultaneously satisfying the requirements of long circulating time, efficient tumor cell targeting, and fast intracellular drug release.     

Self‐Assembled Nanoparticles with Dual Effects of Passive Tumor Targeting and Cancer‐Selective Anticancer Effects

Nanoparticular drug delivery systems may help to overcome the limitations of conventional chemotherapy. They have been reported to improve the specificity of distribution, the bioavailability, and the solubility of drugs, as well as the duration of drug efficacy, and helping to overcome multidrug resistance. Although various polymeric nanoparticles have been developed for delivery of anticancer agents, most nanoparticles still focus on solubilizing drugs, improving targeting ability, and reducing side effects. In particular, targeting to the tumor is typically improved through passive or active targeting. Despite great achievements in both strategies, yet to be resolved are issues of toxicity in normal cells and enhancement of tumor‐specificity. A new approach combining the dual strategies of passive tumor targeting and cancer‐selective efficacy is proposed. Recombinant human gelatin conjugated with lipoic acid (rHG‐LA) developed in this study forms nanoparticles spontaneously in aqueous solution and encapsulates alpha‐tocopheryl succinate (α‐TOS), a well‐known cancer‐selective apoptosis‐inducing agent, within a hydrophobic core during the self‐assembly. This study describes the promising applicability of α‐TOS‐loaded rHG‐LA nanoparticles with passive targeting ability and cancer‐specificity.     

Enhanced Nanodrug Delivery to Solid Tumors Based on a Tumor Vasculature‐Targeted Strategy

Tumor angiogenesis is a hallmark of tumor growth and metastasis, and inhibition of tumor angiogenesis is an effective strategy for tumor therapy. The high expression levels of specific biomarkers such as integrin receptors (e.g., α_vβ₃) in the endothelium of tumor vessels make angiogenesis an ideal target for drug delivery and thus tumor therapy. Herein, a new nanodrug (T&D@RGD‐Ag₂S) is presented, which can effectively inhibit tumor growth by integrating the specific recognition peptide cyclo(Arg‐Gly‐Asp‐d‐Phe‐Cys) (cRGD) for tumor vascular targeting, the broad‐spectrum endothelial inhibitor O‐(chloroacetyl‐carbamoyl) fumagillol (TNP‐470), and chemotherapeutic drug doxorubicin (DOX) for synergetic tumor therapy. The results show that the T&D@RGD‐Ag₂S nanodrug rapidly and specifically binds to the tumor vasculature after intravenous injection. Tumor vascular density is greatly reduced following effective angiogenesis inhibition by TNP‐470. Meanwhile, increased delivery of DOX deep into the tumor induces extensive tumor apoptosis, resulting in remarkable tumor growth inhibition in a human U87‐MG malignant glioma xenograft model. In addition, the therapeutic effects of T&D@RGD‐Ag₂S on inhibiting tumor growth and decreasing vessel density are monitored in situ using near‐infrared II (NIR‐II) fluorescence imaging of Ag₂S quantum dots. This tumor vasculature‐targeted strategy can be extended as a general method for treating a broad range of tumors and holds promise for future clinical applications.     

Noncovalent Polymer‐Gatekeeper in Mesoporous Silica Nanoparticles as a Targeted Drug Delivery Platform

Selective targeting of tumor cells and release of drug molecules inside the tumor microenvironment can reduce the adverse side effects of traditional chemotherapeutics because of the lower dosages required. This can be achieved by using stimuli‐responsive targeted drug delivery systems. In the present work, a robust and simple one‐pot route is developed to synthesize polymer‐gatekeeper mesoporous silica nanoparticles by noncovalent capping of the pores of drug‐loaded nanocontainers with disulfide cross‐linkable polymers. The method offers very high loading efficiency because chemical modification of the mesoporous nanoparticles is not required; thus, the large empty pore volume of pristine mesoporous silica nanoparticles is entirely available to encapsulate drug molecules. Furthermore, the polymer shell can be easily decorated with a targeting ligand for selective delivery to specific cancer cells by subsequent addition of the thiol‐containing ligand molecule. The drug molecules loaded in the nanocontainers can be released by the degradation of the polymer shell in the intracellular reducing microenvironment, which consequentially induces cell death.     

The Antitumor Efficacy of CpG Oligonucleotides is Improved by Encapsulation in Plant Virus‐Like Particles

Oligodeoxynucleotides (ODNs) with CpG motifs have potent immunostimulatory effects on many subsets of immune cells. For example, Class B CpG‐ODNs, such as ODN1826 induce the phagocytic activity of macrophages by activating the Toll‐like receptor 9 signaling pathway. Systemic ODN delivery results in unfavorable pharmacokinetic profiles and can trigger adverse effects. To address this issue, plant virus‐like particles (VLPs) are developed for the targeted delivery of ODN1826 to tumor‐associated macrophages (TAMs). ODN1826 is encapsulated by the in vitro disassembly and reassembly of Cowpea chlorotic mottle virus (CCMV), producing VLPs that are structurally analogous to the native virus. The encapsulation of ODN1826 in CCMV‐derived VLPs promotes ODN uptake by TAMs ex vivo and significantly enhance their phagocytic activity. The antitumor activity of the VLPs in vivo is also evaluated, revealing that the direct injection of ODN1826 VLPs into established tumors induces a robust antitumor response by increasing the phagocytic activity of TAMs in the tumor microenvironment. CCMV encapsulation significantly enhances the efficacy of ODN1826 compared to the free drug, slowing tumor growth and prolonging survival in mouse models of colon cancer and melanoma.     

Smart Supramolecular “Trojan Horse”‐Inspired Nanogels for Realizing Light‐Triggered Nuclear Drug Influx in Drug‐Resistant Cancer Cells

Efficient nuclear delivery of anticancer drugs evading drug efflux transporters (DETs) on the plasma and nuclear membranes of multidrug‐resistant cancer cells is highly challenging. Here, smart nanogels are designed via a one‐step self‐assembly of three functional components including a biocompatible copolymer, a fluorescent organosilica nanodot, and a photodegradable near‐infrared (NIR) dye indocyanine green (ICG). The rationally designed nanogels have high drug encapsulation efficiency (≈99%) for anticancer drug doxorubicin (Dox), self‐traceability for bioimaging, proper size for passive tumor targeting, prolonged blood circulation time for enhanced drug accumulation in tumor, and photocontrolled disassemblability. Moreover, the Dox‐loaded nanogels can effectively kill multidrug‐resistant cells via two steps: 1) They behave like a “Trojan horse” to escape from the DETs on the plasma membrane for efficiently transporting the anticancer “soldier” (Dox) into the cytoplasm and preventing the drugs from being excreted from the cells; 2) Upon NIR light irradiation, the photodegradation of ICG leads to the disassembly of the nanogels to release massive Dox molecules, which can evade the DETs on the nuclear membrane to exert their intranuclear efficacy in multidrug‐resistant cells. Combined with their excellent biocompatibility, the nanogels may provide an alternative solution for overcoming cancer multidrug resistance.     

Triphenylphosphonium‐Conjugated Poly(ε‐caprolactone)‐Based Self‐Assembled Nanostructures as Nanosized Drugs and Drug Delivery Carriers for Mitochondria‐Targeting Synergistic Anticancer Drug Delivery

For mitochondria‐targeting delivery, a coupling reaction between poly(ε‐caprolactone) diol (PCL diol) and 4‐carboxybutyltriphenylphosphonium (4‐carboxybutyl TPP) results in the synthesis of amphiphilic TPP‐PCL‐TPP (TPCL) polymers with a bola‐like structure. In aqueous environments, the TPCL polymer self‐assembled via cosolvent dispersion and film hydration, resulting in the formation of cationic nanoparticles (NPs) less than 50 nm in size with zeta‐potentials of approximately 40 mV. Interestingly, different preparation methods for TPCL NPs result in various morphologies such as nanovesicles, nanofibers, and nanosheets. In vitro cytotoxicity results with TPCL NPs indicate IC₅₀ values of approximately 10–60 μg mL^?1, suggesting their potential as anticancer nanodrugs. TPCL NPs can be loaded both with hydrophobic doxorubicin (Dox) and its hydrophilic salt form (Dox·HCl), and their drug loading contents are approximately 2–10 wt% depending on the loading method and the hydrophilicity/hydrophobicity of the drugs. Although Dox·HCl exhibits more cellular and nuclear uptake, resulting in greater antitumor effects than Dox, most drug‐loaded TPCL NPs exhibit higher mitochondrial uptake and approximately 2–7‐fold higher mitochondria‐to‐nucleus preference than free drugs, resulting in superior (approximately 7.5–18‐fold) tumor‐killing activity for most drug‐loaded TPCL NPs compared with free drugs. In conclusion, TPCL‐based nanoparticles have potential both as antitumor nanodrugs themselves and as nanocarriers for chemical therapeutics.     

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.     

Remotely Controlled Red Blood Cell Carriers for Cancer Targeting and Near‐Infrared Light‐Triggered Drug Release in Combined Photothermal–Chemotherapy

Red blood cells (RBCs), the “innate carriers” in blood vessels, are gifted with many unique advantages in drug transportation over synthetic drug delivery systems (DDSs). Herein, a tumor angiogenesis targeting, light stimulus‐responsive, RBC‐based DDS is developed by incorporating various functional components within the RBC platform. An albumin bound near‐infrared (NIR) dye, together with a chemotherapy drug doxorubicin, is encapsulated inside RBCs, the surfaces of which are modified with a targeting peptide to allow cancer targeting. Under stimulation by an external NIR laser, the membrane of the RBCs would be destroyed by the light‐induced photothermal heating, resulting in effective drug release. As a proof of principle, RBC‐based cancer cell targeted drug delivery and light‐controlled drug release is demonstrated in vitro, achieving a marked synergistic therapeutic effect through the combined photothermal–chemotherapy. This work presents a novel design of smart RBC carriers, which are inherently biocompatible, promising for targeted combination therapy of cancer.     

Dual‐Targeting Heparin‐Based Nanoparticles that Re‐Assemble in Blood for Glioma Therapy through Both Anti‐Proliferation and Anti‐Angiogenesis

The efficient and specific delivery of nanoparticles (NPs) to brain tumors is crucial for successful glioma treatment. Heparin‐based polymers decorated with two peptides self‐assemble into multi‐functional NPs that specifically target glioma cells. These NPs re‐self‐assemble to a smaller size in blood, which is beneficial for in‐vivo brain drug delivery. The hydrodynamic size of one type of these NPs is 63 ± 11 nm under blood‐mimic conditions (10% fetal bovine serum), but it is 164 ± 16 nm in water. Additionally their zeta potential is more neutral in the blood‐mimic conditions. Transmission electron microscopy reveals the morphology of the spherical NPs. In vitro experiments demonstrate that the NPs exhibit a high cellular uptake and the ability to efficiently discourage proliferation, endothelial‐lined vessels, and vasculogenic mimicry. In vivo studies demonstrate that the NPs can by‐pass the normal blood–brain and blood–(brain tumor) barriers and specifically accumulate in glioma tissues; moreover, they present an excellent anti‐glioma effect in subcutaneous/intracranial glioma‐bearing mice. Their superiority is due to their appropriate size in blood and the synergic effect arising from their targeting of two different receptors. The data suggests that these NPs are ideal for anti‐glioma therapy.