Emerging Approaches of Cell‐Based Nanosystems to Target Cancer Metastasis

Cancer metastasis accounts for the high mortality of cancer‐related deaths and the therapy is greatly challenged by the limited drug delivery efficiency. Inspired by the essential role of culprit cancer cells and versatile accessory cells during cancer metastasis, diverse cell‐based nanosystems (CBNs) are emerging as attractive and encouraging drug delivery platforms to target cancer metastasis. Herein, the authors focus on the emerging strategies of versatile CBNs that synergistically combine the merit of source cells and nanoparticles for antimetastasis therapy. CBNs are usually comprised of natural nanosized vesicles, cell membrane camouflaged nanoparticles, and bioengineered living cell vehicles. The authors discuss the rationality and advances of various CBNs in targeting different stages of cancer metastasis, including primary tumor, circulating tumor cells (CTCs), and distant metastasis as well as the tumor immune microenvironments (TIM). On this basis, this review provides some feasible perspectives on designing CBNs to enhance the drug delivery efficiency for treating cancer metastasis.     

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.     

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.     

Bioinspired Nanoparticles with NIR‐Controlled Drug Release for Synergetic Chemophotothermal Therapy of Metastatic Breast Cancer

Optimal nanosized drug delivery systems (NDDS) require long blood circulation and controlled drug release at target lesions for efficient anticancer therapy. Red blood cell (RBC) membrane‐camouflaged nanoparticles (NPs) can integrate flexibility of synergetic materials and highly functionality of RBC membrane, endowed with many unique advantages for drug delivery. Here, new near‐infrared (NIR)‐responsive RBC membrane‐mimetic NPs with NIR‐activated cellular uptake and controlled drug release for treating metastatic breast cancer are reported. An NIR dye is inserted in RBC membrane shells, and the thermoresponsive lipid is employed to the paclitaxel (PTX)‐loaded polymeric cores to fabricate the RBC‐inspired NPs. The fluorescence of dye in the NPs can be used for in vivo tumor imaging with an elongated circulating halftime that is 12.3‐folder higher than that of the free dye. Under the NIR laser stimuli, the tumor cellular uptake of NPs is significantly enhanced to 2.1‐fold higher than that without irradiation. The structure of the RBC‐mimetic NPs can be destroyed by the light‐induced hyperthermia, triggered rapid PTX release (45% in 30 min). These RBC‐mimetic NPs provide a synergetic chemophotothermal therapy, completely inhibited the growth of the primary tumor, and suppress over 98% of lung metastasis in vivo, suggesting it to be an ideal NDDS to fight against metastatic breast cancer.     

Activated Platelets‐Targeting Micelles with Controlled Drug Release for Effective Treatment of Primary and Metastatic Triple Negative Breast Cancer

The frequent relapse and metastasis characteristics of triple negative breast cancer (TNBC) make it a fraught issue with very poor prognosis in clinic. An effective treatment for TNBC should prevent and even eliminate metastasis as well as suppress primary lesion expansion. Recent progress reveals that platelets can be recruited and activated by tumor cells through intercellular adhesion molecules (ICAM), and help aggressive circulating tumor cells (CTCs) form metastasis. Therefore, activated platelets are considered with possession of tumor‐homing, CTC‐capturing, and metastasis‐targeting abilities. In this work, a P‐selectin (expressed on activated platelet surface) targeting peptide (PSN) is modified on a redox‐responsive paclitaxel‐loaded micelle (PSN‐PEG‐SS‐PTX₄ micelle) to utilize activated platelets as a “bridge” for interaction with cancer cells. The PSN‐modified micelle can easily adhere to the surface of activated platelets and subsequently capture CTCs in blood circulation. Compared to Taxol and PEG‐SS‐PTX₄ micelle, PSN‐PEG‐SS‐PTX₄ micelle also exhibits enhanced primary TNBC/metastasis targeting and penetrating effect through binding with tumor infiltrating platelets and thus significantly improves treatment outcome. More importantly, PSN‐PEG‐SS‐PTX₄ micelle potently suppressed lung metastasis of TNBC and reduced incidence of distant liver metastasis. The activated platelet‐targeting redox‐responsive micelle system provides a promising prospect for the omnidirectional treatment of metastatic cancer.     

Ly6Chi Monocytes Delivering pH‐Sensitive Micelle Loading Paclitaxel Improve Targeting Therapy of Metastatic Breast Cancer

Many immune cells are capable of homing to sites of disease and eradicating infections and abnormal cells. However, their efficacy is usually down‐regulated in tumor microenvironments and it is difficult to boost. It is presumed that the anticancer activity of immune cells can be improved by integrating an additional therapeutic modality such as chemotherapy into the cells. Here, Ly6C^hi monocytes armed with the paclitaxel (PTX)‐loading pH‐sensitive micelle (PM), termed as PM@MC, are prepared. The PM internalization does not significantly affect the properties of the host Ly6C^hi monocytes. In the 4T1 metastatic breast cancer mice model, PM@MCs home to both primary tumor and the lung metastasis foci. PM@MC exhibit 15‐fold higher intratumor PTX accumulation than the commercial PTX injection, and achieve a tumor inhibiting rate of 96.8% and a lung metastasis suppression rate of 99.2%. No significant change is recorded in histology of major organs and in hematological and biochemical parameters after PM@MC treatment. The pH‐sensitive micelle/Ly6C^hi monocyte drug delivery device thus has the application potential in the targeting therapy of breast cancer with metastasis.     

Histone Deacetylase-Triggered Self-Immolative Peptide-Cytotoxins for Cancer-Selective Drug Delivery

Precise delivery and release of therapeutics in the subcellular targets are critical for tumor-selective chemotherapy. Self-immolative structures are sophisticatedly designed to achieve stimuli-responsive drug delivery. Herein, the facile fabrication of self-immolative peptide-camptothecin (CPT) nanoassemblies is reported for cancer-selective drug delivery by utilizing the dual-mode peptide targeting design and amine-catalyzed intramolecular hydrolysis. The dual-mode peptide targeting design is realized by co-assembly of tumor targeting and nuclei-localizing peptide-CPT prodrugs, rendering the nanoassemblies with efficient cancer cell-selective capability. When the nanoassemblies enter cancer cell, the overexpressed endonuclear histone deacetylases (HDACs) cleave the acetyl group to generate primary amines, triggers amine-catalyzed intramolecular hydrolysis, and fast-release drug in the cell nuclei. The peptide-CPT prodrugs release up to 68% CPT in 1 h in the presence of HDACs, while no detectable CPT release is observed in the absence of HDACs at the same time. The peptide-CPT prodrugs selectively kill cancer cells with high HDACs levels. The dual targeting peptide-CPT nanoassemblies exhibit extended blood circulation, excellent tumor accumulation, and potent antitumor activity by inhibiting tumor progression and metastasis in mice bearing 4T1 aggressive breast tumors. Overall, the HDAC-triggered self-immolative strategy is promising for developing cancer-selective drug delivery systems.     

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.     

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.     

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.     

Two‐Step Targeted Hybrid Nanoconstructs Increase Brain Penetration and Efficacy of the Therapeutic Antibody Trastuzumab against Brain Metastasis of HER2‐Positive Breast Cancer

Therapeutic antibodies (e.g., trastuzumab, TRA) against human epidermal growth factor receptor 2 (HER2)‐positive breast cancers have shown benefits in controlling primary tumors, yet are ineffective against brain metastases due to their inability to cross the blood‐brain barrier (BBB). A novel hybrid nanoconstruct system is designed to deliver trastuzumab to brain metastasis of HER2‐positive breast cancer via a two‐step sequential targeting approach. Self‐assembly of a polysorbate 80 (PS 80)‐containing polymer, lipid, and polymer‐conjugated TRA forms hybrid nanoconstructs (TRA–terpolymer nanoparticles (TPN)) with high encapsulation efficiency and bioactivity. The PS 80 moiety enables the first‐step targeting and receptor‐mediated trancytosis across BBB is demonstrated in vitro with a 3D human BBB model in healthy and brain tumor‐bearing mice. The subsequent partial dissociation of the nanoconstructs exposes the encapsulated TRA for the second‐step targeting to HER2‐positive cancer cells in the brain. Intravenously injected TRA–TPN delivers 50‐fold TRA compared to free TRA to the brain metastasis of HER2‐positive breast cancer. Treatment with TRA–TPN increases tumor cell apoptosis by 4‐fold, inhibits tumor growth by 43‐fold, and prolongs median survival by >1.3‐fold compared to free TRA, without causing noticeable organ toxicity. These findings suggest the two‐step targeted nanoconstruct system is promising for shuttling therapeutic antibodies to treat central nervous system diseases.     

Covalent Organic Framework‐Supported Molecularly Dispersed Near‐Infrared Dyes Boost Immunogenic Phototherapy against Tumors

Photodynamic therapy (PDT) mediated by near‐infrared (NIR) dyes is a promising cancer treatment modality; however, its use is limited by significant challenges, such as hypoxic tumor microenvironments and self‐quenching of photosensitizers. These challenges hamper its utility in inducing immunogenic cell death (ICD) and triggering potent systemic antitumor immune responses. This study demonstrates that molecular dispersion of NIR dyes in nanocarriers can significantly enhance their ability to produce reactive oxygen species and potentiate synergistic PDT and photothermal therapy against tumors. Specifically, NIR dye indocyanine green (ICG) can be spontaneously adsorbed to covalent organic frameworks (COFs) via π–π conjugations to prevent intermolecular stacking interactions. Then, ICG‐loaded COFs are ultrasonically exfoliated and coated with polydopamine (PDA) to construct a new phototherapeutic agent ICG@COF‐1@PDA with enhanced efficacy. In conjunction with ICG@COF‐1@PDA, a single round of NIR laser irradiation can induce obvious ICD, elicit antitumor immunity in colorectal cancer, and yield 62.9% inhibition of untreated distant tumors. ICG@COF‐1@PDA also exhibits notable phototherapeutic efficacy against 4T1 murine breast to lung metastasis, a spontaneous metastasis mode for triple‐negative breast cancers (TNBCs). Overall, this study reveals a novel nanodelivery system for molecular dispersion of NIR dyes, which may present new therapeutic opportunities against primary and metastatic tumors.     

Sub-50 nm Supramolecular Nanohybrids with Active Targeting Corona for Image-Guided Solid Tumor Treatment and Metastasis Inhibition

Tumor metastasis is responsible for almost 90% of failure in cancer therapy and it is also the major cause of cancer-associated mortality due to poor vascularization. Herein, a sub-50 nm hybrid theranostic robust nanoplatform is developed via a template supramolecular strategy to achieve active targeting and deep penetration of primary tumors as well as metastatic tumors with poor vascular structures. Quantum dots (QDs) as a template are coordinated with lipoic acid (LA)-functionalized dendrimers for covalent loading of doxorubicin (DOX) and Arg-Gly-Asp (RGD) tripeptide-functionalized polyethylene glycol (PEG) for prolonging blood circulation and selectively targeting cancer cells. When the nanohybrid is internalized into tumor cells, DOX releases from the nanohybrid in acidic lysosomes and is translocated into nuclei for arresting cell cycles at the G2/M phase, leading to a remarkably therapeutic effect for both primary tumors and distant metastases in a 4T1 xenograft tumor model. The inherent fluorescence of QDs in the nanohybrid allows real-time monitoring of the therapeutic responses from primary and metastasis tumors. Hence, a facile strategy is demonstrated to construct a hybrid nanoplatform with multifunctionality for inhibition of both primary and metastatic cancer.     

Biomimetic Nanomedicine Coupled with Neoadjuvant Chemotherapy to Suppress Breast Cancer Metastasis via Tumor Microenvironment Remodeling

The biomimetic enzyme activity of cerium oxide nanoparticles (CeNPs) prefers ultrasmall particle size and bare surface. Unfortunately, those two features are not favorable for its in vivo application due to easy aggregation and fast renal filtration. To take advantage of the activity of CeNP for cancer therapy, a homologous targeted cerium oxide nanoparticle system, targeted CeNP (T-CeNP), with the integration of a biodegradable dendritic mesoporous silica nanoparticle, superoxide dismutase and catalase mimicking CeNPs, and the camouflage coating of cancer cell membrane has been developed. Attributed to the homologous targeting effect of cancer cell membrane, nanoparticles with camouflage coating are retained in the tumor in an orthotopic breast cancer metastatic model. Subsequently, T-CeNP effectively hinders cancer-associated fibroblast transdifferentiation and reprograms it back to a normal fibroblast. Consequently, T-CeNP coupled with doxorubicin reduces the size of primary tumors and prevents the post-surgery lung metastasis and liver metastasis of breast cancer.     

Ternary Regulation of Tumor Microenvironment by Heparanase-Sensitive Micelle-Loaded Monocytes Improves Chemo-Immunotherapy of Metastatic Breast Cancer

Tumor immunotherapy approaches such as programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) checkpoint blockade and indoleamine 2,3-dioxygenase (IDO) inhibition are proven to promote immune response against tumors. Unfortunately, their positive response rates are unsatisfactory due to complicated immunosuppressive mechanisms in the tumor microenvironment, which can probably be rescued by integrating multiple immunoregulators and chemotherapeutic agents together. To improve the combination therapy of metastatic breast cancer, a ternary heparanase (Hpa)-sensitive micelle-loaded monocyte delivery system, termed as HDNH@MC, is designed, exploiting the capacity of Ly6C^hi monocytes to be recruited to tumor sites and the overexpression of Hpa in tumors. The prodrugs of the chemotherapeutic agent docetaxel and IDO inhibitor NLG919 are synthesized by conjugating them on the substrate of Hpa, heparan sulfate. Then the PD-1/PD-L1 inhibitor HY19991-encapsulating prodrug micelle@Ly6C^hi monocyte system is prepared. HNDH@MC elevates drug concentrations and relieves immunosuppression in tumors of 4T1 breast carcinomas mice model, thus enhancing the infiltration and activity of CD8⁺ T cells and presenting significant anti-cancer effect. The lung metastasis is suppressed and the survival of mice is prolonged. HNDH@MC will be a promising option for treating metastatic breast cancer by synergy of tumor-targeting chemotherapy and immunotherapy.     

Targeting CXCR4–CXCL12 Axis for Visualizing,Predicting, and Inhibiting Breast Cancer Metastasis with Theranostic AMD3100–Ag2S Quantum Dot Probe

Breast cancer metastasis remains the primary cause of death and efforts to predict and reduce metastatic risk are particularly appealing. CXC chemokine receptor 4 (CXCR4) is reported as a specific metastasis due to its chemotactic homing to CXCL12. Herein, conjugation of a CXCR4 antagonist, AMD3100, to a fluorescent silver sulfide quantum dot (Ag₂S) core (QD‐AMD) allows accurate detection of CXCR4 expression in tumor. Particularly, the probe precisely distinguishes highly metastatic breast cancer cells from those of lower metastatic ability. Longitudinal in vivo imaging predicts at early stages that the high CXCR4 expressing orthotopic 4T1 tumor would subsequently metastasize to lungs 14 d after tumor inoculation, while no metastasis forms from the low CXCR4 expressing MCF‐7 tumor. Correlative measurements find that the CXCL12 levels in lung increase with tumor progression. Perturbations of either CXCR4 on tumor cells by QD‐AMD or CXCL12 in the lungs by antibody successfully inhibit cancer metastasis. Intravenous injection of QD‐AMD in primary 4T1 tumor model effectively reduces lung metastasis. More importantly, due to the intrinsic photothermal effect, the metastatic spread is more thoroughly abrogated along with substantial shrinkage of primary tumor. Altogether, the probe is promising to detect, predict, and inhibit the metastatic spread of breast tumor.     

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.     

Hierarchically Targeted and Penetrated Delivery of Drugs to Tumors by Size‐Changeable Graphene Quantum Dot Nanoaircrafts for Photolytic Therapy

Theranostic nanohybrids are promising for effective delivery of therapeutic drug or energy and for imaging‐guided therapy of tumors, which is demanded in personalized medicine. Here, a size‐changeable graphene quantum dot (GQD) nanoaircraft (SCNA) that serves as a hierarchical tumor‐targeting agent with high cargo payload is developed to penetrate and deliver anticancer drug into deep tumors. The nanoaircraft is composed of ultrasmall GQDs (less than 5 nm) functionalized with a pH‐sensitive polymer that demonstrates an aggregation transition at weak acidity of tumor environment but is stable at physiological pH with stealth function. A size conversion of the SCNA at the tumor site is further actuated by near‐infrared irradiation, which disassembles 150 nm of SCNA into 5 nm of doxorubicin (DOX)/GQD like a bomb‐loaded jet, facilitating the penetration into the deep tumor tissue. At the tumor, the penetrated DOX/GQD can infect neighboring cancer cells for repeated cell killing. Such a SCNA integrated with combinational therapy successfully suppresses xenograft tumors in 18 d without distal harm. The sophisticated strategy displays the hierarchically targeted and penetrated delivery of drugs and energy to deep tumor and shows potential for use in other tumor therapy.     

Rational Design of Polymeric Hybrid Micelles with Highly Tunable Properties to Co‐Deliver MicroRNA‐34a and Vismodegib for Melanoma Therapy

A polymeric hybrid micelle (PHM) system with highly tunable properties is reported to co‐deliver small molecule and nucleic acid drugs for cancer therapy; this system is structurally simple and easy‐to‐fabricate. The PHM consists of two amphiphilic diblock copolymers, polycaprolactone‐polyethylenimine (PCL‐PEI) and polycaprolactone‐polyethyleneglycol (PCL‐PEG). PHMs are rationally designed with different physicochemical properties by simply adjusting the ratio of the two diblock copolymers and the near neutral PHM‐2 containing a low ratio of PCL‐PEI achieves the optimal balance between high tumor distribution and subsequent cellular uptake after intravenous injection. Encapsulating Hedgehog (Hh) pathway inhibitor vismodegib (VIS) and microRNA‐34a (miR‐34a) into PHM‐2 generates the VIS/PHM‐2/34a co‐delivery system. VIS/PHM‐2/34a shows synergistic anticancer efficacy in murine B16F10‐CD44⁺ cells, a highly metastatic tumor model of melanoma. VIS/PHM‐2/34a synergistically attenuates the expression of CD44, a vital receptor indicating the metastasis of melanoma. Intriguingly, inhibiting Hh pathway by VIS is accompanied by downregulation of CD44 expression, revealing that Hh signaling might be an upstream regulator of CD44 expression in melanoma. Thus, co‐delivery of miR‐34a and VIS demonstrates great potential in cancer therapy, and PHM offers a structurally simple and highly tunable platform for the co‐delivery of small molecule and nucleic acid drugs in tumor combination therapy.     

Tumor Microenvironment‐Responsive Dual Drug Dimer‐Loaded PEGylated Bilirubin Nanoparticles for Improved Drug Delivery and Enhanced Immune‐Chemotherapy of Breast Cancer

The application of combinational therapy makes up for the limitation of monotherapy and achieves superior treatment against cancer. However, the combinational therapy remains restricted by the poor tumor‐specific delivery and the abscopal effect. Herein, reactive oxygen species (ROS)‐responsive PEGylated bilirubin nanoparticles (BRNPs) are developed to encapsulate two glutathione‐activatable drugs, including dimer‐7‐ethyl‐10‐hydroxycamptothecin (d‐SN38) and dimer‐lonidamine (d‐LND). Dimerization of the drugs significantly increases the drug loading capacity and the encapsulation efficiency of nanoparticles. With the assistance of iRGD peptide (cRGDKGPDC), the cellular uptake of BRNPs is more than double when compared with the control. In response to high levels of intracellular ROS, d‐SN38 and d‐LND are rapidly released from nanoparticles (SL@BRNPs). Furthermore, the pharmacodynamic experiments verify combining SL@BRNPs with anti‐PD‐L1 antibody greatly inhibits the primary tumor of breast cancer, improves CD8+ T cells levels, and CD8+ T cells/Tregs ratios in the tumor. Additionally, it shows high immune memory effect and can prevent the growth of lung metastasis. Taken together, the strategy pioneers a new way for the rational design of nanoassemblies through the combination of activatable drug dimers and stimuli‐responsive drug release, and a successful application of novel drug delivery systems in combination with the immune checkpoint blockade antibody.