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.     

Combination of Bacterial‐Photothermal Therapy with an Anti‐PD‐1 Peptide Depot for Enhanced Immunity against Advanced Cancer

Photothermal therapy (PTT) is a promising cancer treatment, but it has so far proven successful only with relatively small subcutaneous tumors in animal models. Treating larger tumors (≈200 mm³) is challenging because most PTT materials do not efficiently reach the hypoxic, avascular center of tumors, and the immunosuppressive tumor microenvironment prevents T cells from fighting against residual tumor cells, thereby allowing recurrence and metastasis. Here, the widely used PTT material polydopamine is coated on the surface of the facultative anaerobe Salmonella VNP20009, which can penetrate deep into larger tumors. The coated bacteria are intravenously injected followed by near‐infrared laser irradiation at the tumor site, combined with a local inoculation of phospholipid‐based phase separation gel containing the anti‐programmed cell death‐1 peptide AUNP‐12. The gel releases AUNP‐12 sustainably during 42 days, maintaining the tumor microenvironment as immunopermissive. Using a mouse model of melanoma, this triple combination of biotherapy, PTT, and sustainable programmed cell death‐1 (PD‐1) blockade shows high efficiency on eliciting robust antitumor immune responses and eliminating relatively large tumors in 50% of animals within 80 days. Thus, the results shed new light on a previously unrecognized immunological facet of bacteria‐mediated therapy, and this innovative triple therapy may be a powerful cancer immunotherapy tool.     

Tumor Cells‐Selective Bionic Nanodevice Exploiting Heparanase Combats Metastatic Breast Cancer

The clinical application of the cytotoxic chemotherapeutic agents in the treatment of metastatic breast cancer is limited by their poor selectivity to cancer cells. In this work, a bionic nanodevice consisting of the docetaxel (DTX)‐heparan sulfate (HS) conjugate (HS‐DTX) micelle with a red blood cells membrane (RBC) coating on its surface, termed as rHS‐DTX, is first constructed. It is found that the cytotoxicity of DTX is concealed by HS in human mammary epithelial Michigan Cancer Foundation (MCF)‐10A cells but restored in human mammary cancer MCF‐7 cells because HS is hydrolyzed by heparanase (Hpa), which is overexpressed only in MCF‐7 but not MCF‐10A cells. The RBC coating enhances the cellular uptake of HS‐DTX and endows it with the long circulating ability in blood. In the MCF‐7 metastatic breast cancer mice model, rHS‐DTX exhibits 6.35‐fold higher intratumor DTX accumulation than the free DTX injection and achieves a tumor inhibiting rate of 98.2% and a lung metastasis suppression rate of 99.6%. No severe toxicity is observed in the major organs and blood of mice treated with rHS‐DTX. In summary, rHS‐DTX can provide a promising strategy for targeting therapy of metastatic breast cancer by improving the tumor‐suppressing efficacy of DTX.     

A Versatile Plasma Membrane Engineered Cell Vehicle for Contact‐Cell‐Enhanced Photodynamic Therapy

In this paper, a plasma membrane engineering approach is reported for tumor targeting drug delivery and contact‐cell‐enhanced photodynamic therapy (“CONCEPT”) by anchoring functionalized conjugates to cell vehicles. The membrane anchoring conjugates are comprised of a positively charged tetra‐arginine peptide sequence, a palmitic‐acid‐based membrane insertion moiety, and a lysine linker whose ε‐amine is modified with camptothecin (CPT), protoporphyrin IX (PpIX), or fluorescein (FAM). The amphipathic CPT, PpIX, or FAM conjugates (short as aCPT, aPpIX, or aFAM, respectively) can easily and steadily anchor or coanchor on the cell membrane of RAW264.7 cells (short as RCs), red blood cells, or mesenchymal stem cells. After anchoring aPpIX in RC cells, the tumor targeting ability and therapeutic effect of aPpIX‐anchored RC cells (short as aPRCs) is demonstrated in vitro and in vivo. Importantly, aPRCs exhibit the “CONCEPT” effect, which can enhance the therapeutic efficacy and reduce side effects at the single cell level. Due to the good tumor‐targeting ability, aPRCs can efficiently inhibit the tumor growth with no systemic toxicity after photoirradiation by photodynamic therapy.     

Hierarchical Spiky Microstraws‐Integrated Microfluidic Device for Efficient Capture and In Situ Manipulation of Cancer Cells

Techniques for capturing circulating tumor cells (CTCs) play an important role in cancer diagnosis. Recently, various 3D micro/nanostructures have been applied for effective CTC detection, yet in situ manipulation of the captured cancer cells on micro/nano‐structural substrates is rarely achieved. In this work, a hierarchical spiky microstraw array (HS‐MSA)‐integrated microfluidic device is demonstrated that possessed dual functions of cancer cell capture and in situ chemical manipulations of the captured cells. The 3D micro/nanostructure of HS‐MSA could capture cancer cells with high efficiency (≈84%) and strong specificity. Based on the HS‐MSA‐integrated microfluidic device, extracellular drug delivery to the captured cancer cells is achieved in situ with excellent spatial, dose, and temporal controls. In addition, a drug‐screening assay on the captured cancer cells is implemented to investigate the cell apoptosis behavior under the microstraw‐mediated delivery of staurosporine (STS). This microfluidic system not only presents tremendous potential for CTCs detection technology, but also opens up new opportunities for high‐throughput drug screening on cancer cells and understanding the cellular activity.     

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.     

Tumor‐Responsive Small Molecule Self‐Assembled Nanosystem for Simultaneous Fluorescence Imaging and Chemotherapy of Lung Cancer

Cancer therapeutic drugs face various transportation barriers in transit to the tumor site, making the delivery of effective drug concentrations problematic. Moreover, these drugs are very difficult to use due to their adverse off‐target effects. Thus, it is very essential to develop a drug delivery system that can deliver drugs to achieve effective local concentrations without side effects on healthy tissues. Herein, the authors report a self‐assembled nanodrug system in which hydrophobic antitumor drugs are packaged into nanoparticles to improve water solubility, tumor targeting ability, blood retention time, and chemotherapeutic effect. The nanodrugs are degraded into smaller ones when exposed to the tumor microenvironment, extravasated from leaky regions of the tumor vasculature, and displayed matrix metalloproteinase‐2 (MMP‐2)‐induced degradation and antitumor property. To construct this unique system, an amphiphilic multifunctional molecule (Pep‐Cy5) is synthesized by attaching a MMP‐2‐cleavable peptide to a hydrophobic near‐infrared dye, Cy5. Two hydrophobic anticancer drugs are conjugated to Pep‐Cy5 through hydrophobic interactions to form the self‐assembled nanodrug system. The MMP‐2‐induced degradation and hydrophobic antitumor drug interchangeability features of this nanosystem enable the hydrophobic antitumor drugs to exhibit longer blood‐retention times, improved intratumoral accumulation, fewer side effects, and higher anticancer efficacies compared with free drugs.     

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.     

Enhanced Intracellular Protein Transduction by Sequence Defined Tetra‐Oleoyl Oligoaminoamides Targeted for Cancer Therapy

Intracellular protein delivery presents a novel promising prospect for cell biology research and cancer therapy. However, inefficient cellular uptake and lysosomal sequestration hinder productive protein delivery into the cytosol. Here, a library of 16 preselected sequence‐defined oligoaminoamide oligomers is evaluated for intracellular protein delivery. All oligomers, containing polyethylene glycol (PEG) for shielding and optionally folic acid as targeting ligand, manifest cellular internalization of disulfide‐conjugated enhanced green fluorescent protein (EGFP). However, only a PEGylated folate‐receptor targeted two‐arm oligomer (729) containing both arms terminally modified with two oleic acids shows persistent intracellular protein survival and nuclear import of nlsEGFP (which contains a nuclear localization sequence) in folate‐receptor‐positive KB carcinoma cells, validating both effective endolysosomal escape and following subcellular transport. Furthermore, using ribonuclease A as a therapeutic cargo protein, among the tested oligomers, the oleic acid modified targeted two‐arm oligomers exert the most significant tumor cell killing of KB tumor cells. An investigation of structure–activity relationship elucidates that the incorporated oleic acids play a vital role in the enhanced intracellular protein delivery, by promoting stable formation of 25–35 nm lipo‐oligomer protein nanoparticles and by membrane‐active characteristics facilitating intracellular cytosolic 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.     

Amorphous Fe‐Based Nanoagents for Self‐Enhanced Chemodynamic Therapy by Re‐Establishing Tumor Acidosis

Chemodynamic therapy (CDT) by introducing the Fenton‐/Fenton‐like reaction in an acidic and H₂O₂ environment for toxic hydroxyl radical (?OH) generation, is a newly developed tumor‐selective therapeutic. However, tumor acidosis, characterized by extracellular acidity (pH_e ≈ 6.5) and intracellular alkalinity (pH_i ≈ 7.2), undoubtedly confers a large chemical barrier for effective implementation of intracellular CDT and thus limits its functional activity and therapeutic efficacy. Here, the unique amorphous iron nanoparticles (AFeNPs) loaded with carbonic anhydrase IX inhibitor (CAI) are constructed to re‐establish tumor acidosis with decreased pH_i and increased pH_e via inhibiting the over‐expressed CA IX in cancer cells by CAI for self‐enhanced CDT. The suppression of CA IX leads to H⁺ accumulation in cells that could accelerate the AFeNPs‐based Fenton reaction to drastically exacerbate oxidative stress in cells and subsequently induce cell death; meanwhile, the inhibition of H⁺ formation outside cells efficiently represses the potential of tumor invasion and metastasis owing to the insufficient acidic ions for degradation of tumor extracellular matrix. Re‐established tumor acidosis not only assists in the optimization of CDT, but also presents an opportunity for the development of new antitumor methods that are more tumor‐acidity specific.     

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.     

In Situ Photocatalyzed Oxygen Generation with Photosynthetic Bacteria to Enable Robust Immunogenic Photodynamic Therapy in Triple‐Negative Breast Cancer

Hypoxia in the tumor microenvironment is a major hurdle dampening the antitumor effect of photodynamic therapy (PDT). Herein, active photosynthetic bacteria (Synechococcus 7942, Syne) are utilized for tumor‐targeted photosensitizer delivery and in situ photocatalyzed oxygen generation to achieve photosynthesis‐boosted PDT. Photosensitizer‐encapsulated nanoparticles (HSA/ICG) are assembled by intermolecular disulfide crosslinking and attached to the surface of Syne with amide bonds to form a biomimetic system (S/HSA/ICG). S/HSA/ICG combined the photosynthetic capability of Syne and the theranostic effect of HSA/ICG. Syne capable of photoautotrophy exhibit a moderate immune stimulation effect and a certain photodynamic role under 660 nm laser irradiation. Upon intravenous injection into tumor‐bearing mice, S/HSA/ICG can effectively accumulate in tumors and generate oxygen continuously under laser irradiation through photosynthesis, which remarkably relieve tumor hypoxia and enhance reactive oxygen species production, thereby completely eliminating primary tumors. This photosynthesis‐boosted PDT can also effectively reverse the tumor immunosuppressive microenvironment and robustly evoke systematic antitumor immune responses, which exhibit excellent effect on preventing tumor recurrence and metastasis inhibition in a metastatic triple‐negative breast cancer mouse model. Hence, this photosynthetic bacteria‐based photosynthesis‐boosted immunogenic PDT offers a promising approach to eliminate both local and metastatic tumors.     

Programmed Multiresponsive Vesicles for Enhanced Tumor Penetration and Combination Therapy of Triple‐Negative Breast Cancer

Nanomedicine is a promising approach for combination chemotherapy of triple‐negative breast cancer (TNBC). However, the therapeutic efficacy of nanoparticulate drugs is suppressed by a series of biological barriers. The authors herein present a programmed stimuli‐responsive liposomal vesicle to overcome the sequential barriers for enhanced TNBC therapy. The intelligent vesicles are engineered by integrating an enzyme‐cleavable polyethylene glycol (PEG) corona, a light‐responsive photosensitizer pheophorbide a (PPa), and a temperature‐sensitive liposome (TSL) into a single nanoplatform. The resultant enzyme, light, and temperature multisensitive liposome (ELTSL) is sequentially coloaded with a lipophilic oxaliplatin prodrug of hexadecyl‐oxaliplatin carboxylic acid (HOC) and hydrophilic doxorubicin hydrochloride (DOX). Dual drug‐loaded ELTSL displays enhanced tumor penetration and increased cellular uptake upon matrix metalloproteinase 2 mediated cleavage of the PEG corona. Under NIR laser irradiation, PPa induces mild hyperthermia effect to trigger ultrafast drug release in the tumor cells. In combination with PPa‐mediated photodynamic therapy, HOC and DOX coloaded ELTSL show significantly improved antitumor efficacy than monotherapy. Given the clinically translatable potential of the liposomal vesicles, ELTSL might represent a promising nanoplatform for combination TNBC therapy.     

Multistage Nanovehicle Delivery System Based on Stepwise Size Reduction and Charge Reversal for Programmed Nuclear Targeting of Systemically Administered Anticancer Drugs

The nucleus is the final target of many first‐line chemotherapeutics, but the need to overcome multiple physiological barriers imposes conflicting requirements for size and charge on systemically administered drug delivery systems. Here, an N‐(2‐hydroxypropyl) methacrylamide (HPMA) polymer‐based nanovehicle (PNV) that self‐assembles from anionic HPMA copolymers with charge‐reversal ability and cationic HPMA copolymers with intracellularly detachable subgroups (IDS) is described. The IDS, bearing an anticancer drug and nuclear‐homing cell‐penetrating peptide (R8NLS ligand), is grafted onto the HPMA copolymer via hydrazone linkage. The large, neutrally charged, self‐assembled PNV (≈55 nm) shows good blood persistence and preferential tumor accumulation. After tumoral arrival, the extracellular milieu actuates the disassembly of PNV to linear conjugates (≈10 nm/39 kDa). This first‐stage size reduction exposes R8NLS and allows for deeper tissue penetration and greater cellular internalization. After endocytosis, a second‐stage size reduction occurs when the more acidic endolysosomal pH cleaved the ≈2.4 kDa IDS off the HPMA copolymer backbone and guaranteed the successful nuclear entry via nuclear localization signal assistance. Based on the stepwise size reduction and on‐demand R8NLS exposure, the PNV inhibits growth of HeLa tumors in nude mice by 75%. This work gives important insights into the design of systemic nuclear‐targeted delivery via a multistage size/charge changing way.     

Dual Targeted Immunotherapy via In Vivo Delivery of Biohybrid RNAi‐Peptide Nanoparticles to Tumor‐Associated Macrophages and Cancer Cells

Lung cancer is associated with very poor prognosis and considered one of the leading causes of death worldwide. Here, highly potent and selective biohybrid RNA interference (RNAi)‐peptide nanoparticles (NPs) are presented that can induce specific and long‐lasting gene therapy in inflammatory tumor associated macrophages (TAMs), via an immune modulation of the tumor milieu combined with tumor suppressor effects. The data here prove that passive gene silencing can be achieved in cancer cells using regular RNAi NPs. When combined with M2 peptide–based targeted immunotherapy that immuno‐modulates TAMs cell population, a synergistic effect and long‐lived tumor eradication can be observed along with increased mice survival. Treatment with low doses of siRNA (ED₅₀ 0.0025–0.01 mg kg^?1) in a multi and long‐term dosing system substantially reduces the recruitment of inflammatory TAMs in lung tumor tissue, reduces tumor size (≈95%), and increases animal survival (≈75%) in mice. The results here suggest that it is likely that the combination of silencing important genes in tumor cells and in their supporting immune cells in the tumor microenvironment, such as TAMs, will greatly improve cancer clinical outcomes.     

Size/Charge Changeable Acidity‐Responsive Micelleplex for Photodynamic‐Improved PD‐L1 Immunotherapy with Enhanced Tumor Penetration

The checkpoint blockade‐based immunotherapy has recently emerged as a promising approach for tumor treatment, but its clinical implementation has been impeded by poor tumor penetration of the nanocarriers and activation of antitumor immune response. To overcome the obstacles, a tumor acidity‐responsive micellar nanocomplex co‐loaded with programmed death‐ligand 1 (PD‐L1)‐blockade siRNA and mitochondrion‐targeting photosensitizer for the synergistic integration of photodynamic therapy and immunotherapy is reported in the present study. The nanosystem is coated with long‐circulating polyethylene glycol (PEG) shells, which can be shed in response to the weakly acidic tumor microenvironment and lead to significant size reduction and increasing positive charge. These transitions facilitate penetration and uptake of nanocarriers against tumors. Subsequently, under the mild acidic endo/lysosome condition, the micellar nanocomplexes are rapidly protonated and disintegrated to release the PD‐L1‐blockade siRNA and photosensitizer through sponge effect. Results from in vitro and in vivo experiments collectively reveal that the nanosystem efficiently activates a photodynamic therapy‐induced immune response and silences immune resistance mediated by the checkpoint gene PD‐L1. In consequence, melanoma growth is inhibited and the recurrence rate is reduced via triggering systemic antitumor immune responses. This study offers an alternative strategy for the development of efficient antitumor immune therapy.     

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.     

Localized Multi‐Component Delivery Platform Generates Local and Systemic Anti‐Tumor Immunity

As tumors employ complementary overlapping and/or independent mechanisms to evade immune surveillance, many emerging cancer immunotherapies attempt to target multiple pathways to eradicate malignant cells. Although modulation of independent pathways by simultaneous administration of multiple immune modulators (e.g., checkpoint inhibitors, cytokines, and growth factors) has shown great promise, the clinical impact remains limited due to severe toxicity associated with high systemic levels of many of these drugs. Therefore, novel platforms for efficient delivery of multi‐component therapies at lower effective doses would be enabling. Here, a drug delivery platform called immunomodulatory molecule delivery system (iMods), which provides sustained extracellular delivery of a checkpoint inhibitor (anti‐PD‐L1) and simultaneously, targeted intracellular delivery of a tumor antigen (OVA) along with adjuvant (poly(I:C)), and the indoleamine deoxygenase inhibitor 1‐MT is described. In melanoma tumor‐bearing mice, combinatorial delivery of these factors with iMods leads to regression of both treated and untreated (contralateral) melanoma tumors and 100% survival. These promising therapeutic outcomes are attributed to significantly enhanced ratios of anti‐tumor CD8 T‐cell/tumor‐protective regulatory T‐cell (Treg) in tumors and tumor draining lymph nodes. Overall, the iMods delivery platform described here represents a promising advance in multi‐factor cancer immunotherapy.     

Real‐Time Imaging Tracking of Engineered Macrophages as Ultrasound‐Triggered Cell Bombs for Cancer Treatment

Cell‐based drug delivery systems are a promising platform for tumor‐targeted therapy due to their high drug‐loading capacities and inherent tumor‐homing abilities. However, the real‐time tracking of these carrier cells and controlled release of the encapsulated drugs are still challenging. Here, ultrasound‐activatable cell bombs are developed by encapsulating doxorubicin (DOX) and phase transformable perfluoropentane (PFP) into hollow mesoporous organosilica nanoparticles (HMONs) to prepare DOX/PFP‐loaded HMONs (DPH), followed by internalization into macrophages (RAW 264.7 cells). The resulting cell bombs (DPH‐RAWs) can maintain viability and actively home to the tumor. Especially, their migration can be tracked in real time using ultrasound due to the vaporization of a small portion of PFP during cell incubation at 37 °C. After accumulation at the tumor site, the further vaporization of remaining PFP can be triggered by a short‐pulsed high intensity focused ultrasound (HIFU) sonication, resulting in the generation of several large microbubbles, which destroys DPH‐RAWs and allows drug release out of these cells. The DPH‐RAWs combined with short‐pulsed HIFU sonication significantly inhibit tumor growth and prolong survival of tumor‐bearing mice. In conclusion, this study provides a new approach to cell‐based drug delivery systems for real‐time tracking of their migration and targeted cancer treatment.