Albumin Biomimetic Nanocorona Improves Tumor Targeting and Penetration for Synergistic Therapy of Metastatic Breast Cancer

The synergistic combination of photothermal and RNA interference therapy demonstrates great potential for effective treatment of metastatic breast cancer, but their efficacy is limited by the poor delivery efficiency to tumor. Herein, it is reported that an albumin biomimetic nanocorona (DRI‐S@HSA) can accomplish the high accumulation and deep penetration within tumor tissues, thereby holding great promise for synergistic therapy. DRI‐S@HSA is prepared by camouflaging human serum albumin (HSA) onto an IR‐780 and small interfering RNA‐loaded cell‐penetrating peptide nanoassembly (DRI‐S). In metastatic 4T1 breast cancer cells, DRI‐S@HSA can be largely internalized, and cause significant inhibition on cell migration and proliferation in combination with laser irradiation. Surprisingly, in vivo, the albumin camouflage in DRI‐S@HSA produces a 2.5‐fold enhancement on tumor accumulation compared to the undecorated DRI‐S, and dramatically improves the deep penetration capacity in tumor mass. Moreover, a single DRI‐S@HSA treatment plus 808 nm laser irradiation results in an 83.6% inhibition on tumor growth and efficient prevention of lung metastases. Taken together, the findings can provide an encouraging biomimetic tumor‐targeted drug delivery strategy to inhibit tumor progression and prevent lung metastases of breast cancer.     

Targeted Nanoparticle‐Mediated Gene Therapy Mimics Oncolytic Virus for Effective Melanoma Treatment

Oncolytic virus has potential applications in cancer therapy. However, its clinical application is restricted by the virus‐associated biosafety issues. Here, inspired by the key role of vesicular stomatitis virus matrix protein (VSVMP) in the oncolytic vesicular stomatitis virus (VSV) induced apoptosis, a targeted nanoparticle‐delivered neutral VSVMP gene formulation is designed to act like the VSV for cancer therapy. This VSVMP formulation consists of a CRGDKGPDC peptide modified hybrid monomethoxy poly (ethylene glycol)‐poly(d ,l ‐lactide) nanoparticles complexed with VSVMP plasmid, having good blood compatibility and tumor targeting ability. The transfection efficiency is as high as that of VSV. After intravenous administration, the VSVMP formulation can efficiently target the tumor, significantly inhibit the melanoma growth and metastasis, prolong the survival time of tumor‐bearing mice, and does not cause obvious systemic toxicity. The anticancer mechanisms involve apoptosis induction, angiogenesis inhibition and some virus‐associated signal pathways activation. This work demonstrates a VSV‐inspired nonviral gene therapy that has promising clinical applications in melanoma treatment.     

Highly Biocompatible Carbon Nanodots for Simultaneous Bioimaging and Targeted Photodynamic Therapy In Vitro and In Vivo

Photosensitizers (PSs) are light‐sensitive molecules that are highly hydrophobic, which poses a challenge to their use for targeted photodynamic therapy. Hence, considerable efforts have been made to develop carriers for the delivery of PSs. Herein, a novel design is described of highly biocompatible, fluorescent, folic acid (FA)‐functionalized carbon nanodots (CDs) as carriers for the PS zinc phthalocyanine (ZnPc) to achieve simultaneous biological imaging and targeted photodynamic therapy. FA is modified on PEG‐­passivated CDs (CD‐PEG) for targeted delivery to FA‐positive cancer cells, and ZnPc is loaded onto CD‐PEG‐FA via π–π stacking interactions. CD‐PEG‐FA/ZnPc exhibits excellent targeted delivery of the PS, leading to simultaneous imaging and significant targeted photodynamic therapy after irradiation in vitro and in vivo. The present CD‐based targeted delivery of PSs is anticipated to offer a convenient and effective platform for enhanced photodynamic therapy to treat cancers in the near future.     

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.     

In Situ Formed Fibrin Scaffold with Cyclophosphamide to Synergize with Immune Checkpoint Blockade for Inhibition of Cancer Recurrence after Surgery

Unsatisfied cytoreductive surgery predicts worse clinical outcomes. Previous studies have found that cyclophosphamide (CTX) is a rhythmic immune modulator that can target suppressive regulatory immune cells and meanwhile enhance effector cells. Here, a therapeutic scaffold is engineered based on a fibrin hydrogel to codeliver CTX and anti‐PD‐L1 antibody (aPDL1) for the prevention of cancer recurrence postsurgery. It is demonstrated that the sequential release of CTX and aPDL1 from the fibrin hydrogel can lead to selective depletion of regulatory T cells (Treg) in the residual tumor, which would then synergize the immune checkpoint blockade therapy. The therapeutic benefit is demonstrated in an orthotopic breast tumor and an orthotopic ovarian tumor model after incomplete resection of primary tumors. In this work, the strategy provides a clinically valuable option for preventing cancer recurrence postsurgery.     

Artificial Immunogenic Cell Death Lipid Nanoparticle Functions as a Therapeutic Vaccine for Cancer

Anticancer drug-mediated induction of immunogenic cell death (ICD) blocks metastasis or recurrence in cancer cells by promoting specific immune activity against cancer antigens. However, this strategy has failed to afford adequate treatment efficiency. Overcoming the failure of ICD-mediated cancer therapy, lipid nanoparticles (LNPs) containing cancer cell surface proteins are synthesized using sonication and extrusion without microfluidics. In addition, these LNPs are decorated with high-mobility group box 1 protein and calreticulin, indicators of ICD, and named artificial ICD LNPs (AiLNPs). Administration of AiLNPs effectively targets dendritic cells (DCs) and induces DC activation in mice. Moreover, treating CT-26 tumor-bearing mice with AiLNPs inhibits tumor growth by inducing CT-26 antigen-specific T-cell immunity. Furthermore, AiLNPs containing Lewis lung carcinoma (LLC1) membrane proteins can prevent metastatic LLC1 tumor growth in the lung via LLC1 antigen-specific T-cell activation. Finally, AiLNPs synthesized with human breast cancer membrane proteins activate DC-mediated antigen-specific T-cell immunity, effectively killing tumor cells. Therefore, AiLNPs are expected to be developed as a patient-specific cancer treatment to prevent cancer recurrence and metastasis.     

Tantalum Sulfide Nanosheets as a Theranostic Nanoplatform for Computed Tomography Imaging‐Guided Combinatorial Chemo‐Photothermal Therapy

Near‐infrared (NIR)‐absorbing metal‐based nanomaterials have shown tremendous potential for cancer therapy, given their facile and controllable synthesis, efficient photothermal conversion, capability of spatiotemporal‐controlled drug delivery, and intrinsic imaging function. Tantalum (Ta) is among the most biocompatible metals and arouses negligible adverse biological responses in either oxidized or reduced forms, and thus Ta‐derived nanomaterials represent promising candidates for biomedical applications. However, Ta‐based nanomaterials by themselves have not been explored for NIR‐mediated photothermal ablation therapy. In this work, an innovative Ta‐based multifunctional nanoplatform composed of biocompatible tantalum sulfide (TaS₂) nanosheets (NSs) is reported for simultaneous NIR hyperthermia, drug delivery, and computed tomography (CT) imaging. The TaS₂ NSs exhibit multiple unique features including (i) efficient NIR light‐to‐heat conversion with a high photothermal conversion efficiency of 39%, (ii) high drug loading (177% by weight), (iii) controlled drug release triggered by NIR light and moderate acidic pH, (iv) high tumor accumulation via heat‐enhanced tumor vascular permeability, (v) complete tumor ablation and negligible side effects, and (vi) comparable CT imaging contrast efficiency to the widely clinically used agent iobitridol. It is expected that this multifunctional NS platform can serve as a promising candidate for imaging‐guided cancer therapy and selection of cancer patients with high tumor accumulation.     

A Sequentially Triggered Nanosystem for Precise Drug Delivery and Simultaneous Inhibition of Cancer Growth,Migration, and Invasion

The rational design of cancer‐targeted and bioresponsive drug delivery vehicles can enhance the anticancer efficacy of conventional chemotherapeutics and reduce their adverse side effects. However, the complexity of precise delivery and the ability to trigger drug release in specific tumor sites remain a challenging puzzle. Here, a sequentially triggered nanosystem composed of HER2 antibody with disulfide linkage as a surface decorator (HER2@NPs) is constructed for precise drug delivery and the simultaneous inhibition of cancer growth, migration, and invasion. The nanosystem actively accumulates in cancer cells, undergoes self‐immolative cleavage in response to biological thiols, and is degraded to form small nanoparticles. After internalization by receptor‐mediated endocytosis, the nanoparticles further disassemble under acidic conditions in the presence of lysozymes and cell lysates, leading to sequentially triggered drug release. The released payload triggers overproduction of reactive oxygen species and activates p53 and MAPKs pathways to induce cancer cell apoptosis. Moreover, HER2@NPs markedly suppress the migration and invasion of human bladder cancer cells at nontoxic concentrations. HER2@NPs demonstrate potent in vivo anticancer efficacy, but show no obvious histological damage to the major organs. Taken together, this study provides a valid tactic for the rational design of sequentially triggered nanosystems for precise drug delivery and cancer therapy.     

Pulmonary Targeting Crosslinked Cyclodextrin Metal–Organic Frameworks for Lung Cancer Therapy

Lung cancer is a serious threat to human health with the highest morbidity and mortality; metastatic lung cancer accounts for a majority of cancer-related deaths. Hence, there is considerable interest in developing efficient lung-targeted drug delivery systems to improve overall survival and quality of life of lung cancer patients. Based on the lung-targeting characteristics of cubic crosslinked cyclodextrin metal–organic framework (CDF) nanoparticles, this study shows the synthesis of a nanoplatform using RGD-functionalized CDF to co-deliver low-molecular-weight heparin (LMWH) and doxorubicin (DOX) for treatment of lung cancer. Rational design of the DOX-loaded RGD-CDF-LMWH nanoplatform (RCLD) is carried out. RCLD nanoparticles are efficiently targeted to lung tumors following intravenous administration; RCLD accumulation in the lung is 5.8 times greater than that in the liver. Moreover, RCLD inhibits migration and invasion of cancer cells in vitro and significantly diminishes lung tumor nodule count and area of spread in human A549 and murine B16F10 lung cancer models in vivo. Furthermore, RCLD does not show serum enzyme or histopathologic indicators of tissue damage or adverse hematologic effects. Therefore, the multiple antitumor activities of this novel RCLD nanoplatform, alongside its safety profile for normal tissues, strongly support its use for targeted treatment of lung cancer.     

Self‐Assembled/Drug‐Composed Nanomedicine for Synergistic Photonic Hyperthermia and Targeted Therapy of Breast Cancer by Inhibiting ERK,AKT, and STAT3 Signaling Cascades

Superior to chemotherapy, photonic hyperthermia and targeted therapy have made attractive impacts on cancer treatment by virtue of their profound advantages such as high specificity and minimal invasiveness, but the rational integration of corresponding therapeutic drugs for achieving concurrent photothermal ablation/targeted therapy is still challenging. Herein, a self‐assembled nanomedicine Anlotinib@IR820 is constructed with drug formulations for highly efficient and synergistic photonic hyperthermia and targeted therapy against breast cancer. Specifically, the constructed Anlotinib@IR820 nanomedicine presents high accumulation at the tumor site owing to the enhanced permeability and retention effect and simultaneously overcomes the obstacles of poor water solubility of Anlotinib (for targeted therapy) and the short lifetime of IR820 (for photonic ablation). The photothermal ablation as activated by near‐infrared laser can not only irradiate cancer cells but also promote the cellular uptake of Anlotinib, which presents a profound synergistic function both in vitro and in vivo. Mechanically, Anlotinib@IR820 nanomedicine can induce apoptosis and cause cell cycle arrest in breast cancer through inhibiting ERK, AKT, and STAT3 pathways. Therefore, the rationally designed drug‐composed Anlotinib@IR820 nanomedicine exhibits high clinical translation potential because of its therapeutic nanoformulation, which provides an alternative option for efficient combinational therapy of breast cancer.     

A Smart Nanoassembly for Multistage Targeted Drug Delivery and Magnetic Resonance Imaging

Efficient delivery of DNA‐toxin anticancer drugs into nucleus of targeted tumor cells while simultaneously minimizing the side effects to normal tissue is a major challenge for cancer therapy. Herein, a multistage continuous targeting strategy based on magnetic mesoporous silica nanoparticles to overcome the challenge is demonstrated. At the initial‐stage, the magnetic nanoparticle is capable of efficiently accumulating in tumor tissue guided by magnet. Following by the magnetic targeting, the targeting ligand gets it right into the cancer cell by receptor‐mediated endocytosis. Accompanied by endocytosis into the lysosomes, the nanoparticle reverses its surface charge from negative to positive which leads to the separation of charge‐conversional polymer from the nanoparticle to re‐expose the nuclear‐targeting TAT peptide. Finally, TAT peptide facilitates the carriers to enter nucleus and the DNA‐toxin camptothecin can inhibit topoisomerase I to induce cell apoptosis. Furthermore, the nano‐drug delivery system can be simultaneously used as predominant contrast agents for magnetic resonance imaging. This proof of concept might open the door to a new generation of carrier materials in the fields of targeted drug transport platform for cancer theranostics.     

Sequential Magneto-Actuated and Optics-Triggered Biomicrorobots for Targeted Cancer Therapy

Micro/nanorobots have the potential to be remotely propelled and manipulated in complex biological fluid and organ tissue. However, the combination of the sophisticated physiological barriers, remote-controlled navigation, real-time motion tracking, and diagnostic/therapeutic effects are tremendous challenges for application and translation. An unique sequential magneto-actuated and optics-triggered biomicrorobot (AI microrobot) for actively targeted cancer treatment is prepared. The AI microrobot consists of two components, magnetospirillum magneticum (AMB-1), providing the ability to autonomously swim toward the tumor site via internal hypoxia-driven effects and an external applied magnetic field, and indocyanine green nanoparticles, acting as a fluorescence imaging agent and photothermal therapy. The AI microrobots are tracked in vivo by fluorescence and magnetic resonance imaging. It is found that the AI microrobots can sequentially migrate to the hypoxic internal area of tumors and then effectively eradicate solid tumors through photothermal therapy under NIR laser irradiation. The sequential magneto-actuated and optics-triggered AI microrobots platform described here presents a bioinspired strategy toward remotely controlled propulsion, actively targeted cargo delivery, and satisfactory therapeutic performance in the circulatory system.     

Poly(Ferulic Acid) with an Anticancer Effect as a Drug Nanocarrier for Enhanced Colon Cancer Therapy

As colorectal cancer is the fourth leading cause of cancer‐related death worldwide, colorectal cancer therapy requires new strategies for improved therapeutic effects. Recently, nanodrug carriers have emerged to weaken the systemic toxicity of chemotherapy drugs and strengthen the treatment effectiveness against colorectal cancer. In this report, ferulic acid, a plant derivative, is polycondensed into poly(ferulic acid) (PFA) for the first time to serve as an excellent drug carrier with anticancer performance. PFA self‐assembles into nanoparticles by nanoprecipitation, and the screened PFA nanoparticles (NPs) have a diameter of ≈100 nm and possess a reasonable drug‐loading capacity of ≈8.3% of paclitaxel (PTX). Evaluation of CT26 cells and a corresponding mouse model indicates remarkable inhibition of colon cancer with PTX‐loaded PFA nanoparticles (PFA@PTX NPs) treatment both in vitro and in vivo. Meanwhile, evaluation of blank PFA NPs in a tumor mouse model also shows tumor inhibition, confirming that PFA itself has an anticancer effect in vivo. Overall, the novel nanoparticles based on poly(ferulic acid) can not only effectively deliver chemodrugs but also provide additional anticancer therapeutic effects, providing a promising platform for clinical colon cancer therapy.     

Enzyme-Activated Prodrug-Based Smart Liposomes Specifically Enhance Tumor Hemoperfusion with Efficient Drug Delivery to Pancreatic Cancer Cells and Stellate Cells

Tumor-specific enhanced delivery of chemotherapeutics and modulators to tumor cells and activated pancreatic stellate cells (aPSCs), respectively, represents safer and more effective therapy for pancreatic cancer. Herein, a membrane type 1-matrix metalloproteinase (MT1-MMP)-cleavable spacer is used to assemble low-density cRGDfK onto thermosensitive liposomes loaded with phosphorylated calcipotriol (PCAL) and doxorubicin (DOX), yielding MR-T-PD. The liposome-linked cRGDfK prodrug on MR-T-PD surface is first activated by MT1-MMP, which is selectively expressed on tumor endothelial cells, to release cRGDfK. The free cRGDfK specifically promotes tumor angiogenesis, leading to 3.4-fold higher accumulation and a wider distribution of MR-T-PD in tumors. Furthermore, MR-T-PD rapidly releases PCAL and DOX into the interstitium under heat treatment. The released DOX enters tumor cells to induce apoptosis, whereas the PCAL prodrug is converted to CAL by alkaline phosphatase on the surface of aPSCs; CAL can then enter aPSCs to induce quiescence and promote the antitumor effect of DOX. Finally, by enhancing the exposure of DOX and CAL to tumor cells and aPSCs, respectively, in a tumor-specific manner, MR-T-PD exerts superior efficacy (a 5.9-fold decrease in tumor weight) without causing additional side effects. Overall, this prodrug-based smart liposome system represents a promising paradigm for pancreatic cancer therapy.     

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.     

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.     

Zwitterionic Polysulfamide Drug Nanogels with Microwave Augmented Tumor Accumulation and On‐Demand Drug Release for Enhanced Cancer Therapy

Zwitterionic polymers demonstrate as a class of antifouling materials with long blood circulation in living subjects. Despite extensive research on their antifouling abilities, the responsive zwitterionic polymers that can change their properties by mild outside signals are poorly explored. Herein, a sulfamide‐based zwitterionic monomer is developed and used to synthesize a series of polysulfamide‐based (poly (2‐((2‐(methacryloyloxy)ethyl) dimethylammonio)acetyl) (phenylsulfonyl) amide (PMEDAPA)) nanogels as drug carriers for effective cancer therapy. PMEDAPA nanogels are proved to exhibit prolonged blood circulation without inducing the accelerated blood clearance phenomenon. Intriguingly, PMEDAPA nanogels can sensitively respond to hyperthermia by adjusting the crosslinker degree. After modified with transferrin (Tf), the nanogels (PMEDAPA‐Tf) achieve shielded tumor targeting at normothermia, while exhibiting recovered tumor targeting at hyperthermia, leading to enhanced tumor accumulation. Meanwhile, PMEDAPA‐Tf nanogels show superior penetration ability in 3D tumor spheroids and faster drug release at hyperthermia compared with that at normothermia. In combination with mild microwave heating (≈41 °C), the drug‐loaded PMEDAPA‐Tf nanogels show a pronounced tumor inhibition effect in a humanized orthotropic liver cancer model. Therefore, the study provides a novel hyperthermia‐responsive zwitterionic nanogel that can achieve augmented tumor accumulation and on‐demand drug release assisted with clinically used microwave heating for cancer therapy.     

Magnetic Targeting Enhanced Theranostic Strategy Based on Multimodal Imaging for Selective Ablation of Cancer

The booming development of nanomedicine offers great opportunities for cancer diagnostics and therapeutics. Herein, a magnetic targeting‐enhanced cancer theranostic strategy using a multifunctional magnetic‐plasmonic nano‐agent is developed, and a highly effective in vivo tumor photothermal therapy, which is carefully planed based on magnetic resonance (MR)/photoacoustic (PA) multimodal imaging, is realized. By applying an external magnetic field (MF) focused on the targeted tumor, a magnetic targeting mediated enhanced permeability and retention (MT‐EPR) effect is observed. While MR scanning provides tumor localization and reveals time‐dependent tumor homing of nanoparticles for therapeutic planning, photoacoustic imaging with higher spatial resolution allows noninvasive fine tumor margin delineation and vivid visualization of three dimensional distributions of theranostic nanoparticles inside the tumor. Utilizing the near‐infrared (NIR) plasmonic absorbance of those nanoparticles, selective photothermal tumor ablation, whose efficacy is predicted by real‐time infrared thermal imaging intra‐therapeutically, is carried out and then monitored by MR imaging for post‐treatment prognosis. Overall, this study illustrates the concept of imaging‐guided MF‐targeted photothermal therapy based on a multifunctional nano‐agent, aiming at optimizing therapeutic planning to achieve the most efficient cancer therapy.     

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.     

Photosynthetic Biohybrid Nanoswimmers System to Alleviate Tumor Hypoxia for FL/PA/MR Imaging‐Guided Enhanced Radio‐Photodynamic Synergetic Therapy

Biohybrid microswimmers have recently shown to be able to actively perform in targeted delivery and in vitro biomedical applications. However, more envisioned functionalities of the microswimmers aimed at in vivo treatments are still challenging. A photosynthetic biohybrid nanoswimmers system (PBNs), magnetic engineered bacteria‐Spirulina platensis, is utilized for tumor‐targeted imaging and therapy. The engineered PBNs is fabricated by superparamagnetic magnetite (Fe₃O₄ NPs) via a dip‐coating process, enabling its tumor targeting ability and magnetic resonance imaging property after intravenous injection. It is found that the PBNs can be used as oxygenerator for in situ O₂ generations in hypoxic solid tumors through photosynthesis, modulating the tumor microenvironment (TME), thus improving the effectiveness of radiotherapy (RT). Furthermore, the innate chlorophyll released from the RT‐treated PBNs, as a photosensitizer, can produce cytotoxic reactive oxygen species under laser irradiation to achieve photodynamic therapy. Excellent tumor inhibition can be realized by the combined multimodal therapies. The PBNs also possesses capacities of chlorophyll‐based fluorescence and photoacoustic imaging, which can monitor the tumor therapy and tumor TME environment. These intriguing properties of the PBNs provide a promising microrobotic platform for TME hypoxic modulation and cancer theranostic applications.