Engineering Oncolytic Adenoviruses with VSVG-Decorated Tumor Cell Membranes for Synergistically Enhanced Antitumor Therapy

Oncolytic viruses hold great promise for cancer treatment but their practical applications are seriously impaired by a series of limitations. Herein, an engineered oncolytic adenovirus (OA) is constructed that can boost both the direct oncolysis and antitumor immune response of OA attributed to the increased tumor targeting and low-pH responsive fusogenic activity. The tumor cell membranes are decorated with vesicular stomatitis virus glycoprotein (VSVG) via vesicular stomatitis virus (VSV) infection and then used to mask OA (V-M@OA). After systemic administration, the engineered OA can target homologous tumors owing to the homing ability of tumor membranes. Then the unique low-pH responsive fusogenic activity of VSVG significantly enhances the replication of OA by promoting the whole virus infection process, resulting in remarkable virus-mediated tumoricidal effects and thus abundant in situ released tumor-associated antigens (TAAs). Meanwhile, VSVG on V-M@OA augments the adjuvanticity of OA and thus significantly enhancing the antitumor immune response. The synergism of virus-mediated killing and immune effects leads to significant tumor inhibition with no obvious side effects.     

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.     

Stimuli‐Responsive Scaffold for Breast Cancer Treatment Combining Accurate Photothermal Therapy and Adipose Tissue Regeneration

Development of new therapeutic scaffolds to selectively destruct tumors under gentle conditions meanwhile promoting adipose tissue formation would be a promising strategy for clinical treatment of breast cancer. Herein, a stimuli‐responsive scaffold composed of polyacrylic acid‐g‐polylactic acid (PAA‐g‐PLLA) modified graphene oxide (GO) with a cleavable bond in between (GO‐PAA‐g‐PLLA), gambogic acid (GA), and polycaprolactone (PCL) is fabricated and then preseeded on adipose‐derived stem cells (ADSCs) for breast cancer treatment. This GO–GA‐polymer scaffold is able to simultaneously perform pH‐triggered low temperature (45 °C) photothermal therapy to selectively induce the apoptosis of tumor cells and significantly improve ADSCs growth without any photothermal damage. The low‐temperature photothermal therapy of the scaffolds can induce more than 95% of cell death for human breast cancer (MCF‐7) in vitro, which further completely inhibits tumor growth and finally eliminates tumor tissue in mice. Meanwhile, the prepared GO–GA‐polymer scaffold possesses the improved capability to stimulate the differentiation of ADSCs into adipocytes by upregulating adipo‐related gene expression, and significantly promotes new adipose tissue formation whether with or without NIR irradiation. These results successfully demonstrate that the prepared GO–GA‐polymer scaffolds with bifunctional properties will be a promising candidate for clinical cases involving both tumor treatment and tissue engineering.     

Co‐delivery of Cell‐permeable Chimeric Apoptosis AVPIR8 Peptide/p53 DNA for Cocktail Therapy

The tetra‐peptide AVPI, derived from the Smac/DIABLO N‐terminal epitope, is able to trigger caspase activation and apoptotic process. However, its clinical value is greatly hampered by the nature of membrane‐impermeability. Herein, the cell‐penetrating chimeric apoptotic peptide of AVPIR₈ is synthesized, of which the apoptosis‐induced AVPI is strategically blended with the cell‐penetrating sequence of octaarginine (R₈). The dual‐functionalized AVPIR₈ is not only potent in inducing apoptosis in tumor cells due to the cell penetration ability, but also is able to work as gene carrier for transfering the tumor suppressor p53 DNA into cells, thus constructing a co‐delivery drug system (AVPIR₈/p53). Such system efficiently promotes apoptosis in cancer cells while sparing normal cells, and its antitumor activity is further significantly enhanced in combination with doxorubicin as cocktail therapy. More importantly, the anticancer efficacy of the cocktail is demonstrated to be able to arrest tumor growth in two animal tumor models (melanoma and cervical cancers), respectively. The chemotherapeutic dose in the AVPIR₈/p53‐based cocktail is significantly reduced by 80%, compared to the monotherapy of doxorubicin. The present results show the promise of the co‐delivered AVPIR₈/p53 as adjuvant therapy for boosting the conventional chemotherapeutics, with a unique benefit of enhanced productive treatment outcomes yet greatly reduced adverse toxicity.     

Folic‐Acid‐Mediated Functionalized Gold Nanocages for Targeted Delivery of Anti‐miR‐181b in Combination of Gene Therapy and Photothermal Therapy against Hepatocellular Carcinoma

Therapeutic strategies based on modulation of microRNAs (miRNAs) activity hold much promise for cancer therapy, but for clinical applications, the efficient delivery of miRNAs to tumor cells or tumor tissues remains a great challenge. In this work, microRNA‐181b inhibitor (anti‐miR‐181b) is successfully condensed into polyethyleneimine (PEI)‐modified and folate receptor (FR)‐targeted PEGylated gold nanocages (AuNCs). This delivery system is designated as anti‐miR‐181b/PTPAuNCs nanocomplexes (PTPAuNC‐NPs), which begin with chemical modification of AuNCs with SH‐PEG₅₀₀₀‐folic acid (SH‐PEG₅₀₀₀‐FA) and SH‐PEG₅₀₀₀ through a gold–sulfur bond, followed by conjugating PEI using lipoic acid as a linker. Finally anti‐miR‐181b is condensed via electrostatic interactions. In vitro and in vivo experiments show that PTPAuNC‐NPs can efficiently deliver anti‐miR‐181b into target sites to suppress tumor growth, and considerably decrease tumor volumes in SMMC‐7721 tumor‐bearing nude mice under near‐infrared radiation. All these results suggest that PTPAuNC‐NP gene delivery system with combination of gene therapy and photothermal therapy will be of great potential use in future cancer therapy.     

Multifunctional Micelles for Cancer Cell Targeting,Distribution Imaging,and Anticancer Drug Delivery

Multifunctional micelles for cancer cell targeting, distribution imaging, and anticancer drug delivery were prepared from an environmentally‐sensitive graft copolymer, poly(N‐isopropyl acrylamide‐co‐methacryl acid)‐g‐poly(D ,L ‐lactide) (P(NIPAAm‐co‐MAAc)‐g‐PLA), a diblock copolymer, methoxy poly(ethylene glycol)‐b‐poly(D ,L ‐lactide) (mPEG‐PLA) and two functionalized diblock copolymers, galactosamine‐PEG‐PLA (Gal‐PEG‐PLA) and fluorescein isothiocyanate‐PEG‐PLA (FITC‐PEG‐PLA). Anticancer drug, free base doxorubicin (Dox) was incorporated into the inner core of multifunctional micelles by dialysis. From the drug release study, a change in pH (from pH 7.4 to 5.0) deformed the structure of the inner core from that of aggregated P(NIPAAm‐co‐MAAc), causing the release of a significant quantity of doxorubicin (Dox) from multifunctional micelles. Multifunctional micelles target specific tumors by an asialoglycoprotein (HepG2 cells)‐Gal (multifunctional micelle) receptor‐mediated tumor targeting mechanism. This mechanism then causes intracellular pH changes which induce Dox release from multifunctional micelles and that micelles have strong effects on the viability of HepG2 cells and are abolished by galactose. Confocal laser scanning microscopy (CLSM) reveals a clear distribution of multifunctional micelles. With careful design and sophisticated manipulation, polymeric micelles can be widely used in cancer diagnosis, cancer targeting, and cancer therapy simultaneously.     

Pegylated Composite Nanoparticles Containing Upconverting Phosphors and meso‐Tetraphenyl porphine (TPP) for Photodynamic Therapy

The utilization of upconverting nanophosphors (UCNP) for photodynamic therapy (PDT) has gained significant interests due to its ability to convert deep‐penetrating near‐infra red (NIR) light (i.e., 978 nm) to visible light. Previous attempts to co‐localize UCNPs with photosensitizers suffer from low photo­sensitizer loading and problems with nanoparticle aggregation. Here, the preparation of a novel composite nanoparticle formulation comprising 100 nm β?NaYF₄:Yb³⁺,Er³⁺ UCNPs, and meso‐tetraphenyl porphine (TPP) photo­sensitizer, stabilized by biocompatible poly(ethylene glycol‐block‐(dl )lactic acid) block copolymers (PEG‐b‐PLA) is presented. A photosensitizer loading of 10 wt% with respect to UCNP crystal was achieved via the Flash NanoPrecipitation (FNP) process. A sterically stabilizing PEG layer on the composite nanoparticle surface prevents nanoparticle aggregation and ensures nanoparticle stability in water, PBS buffer, and culture medium containing serum proteins, resulting in nanoparticle suitable for in vivo applications. Based on in vitro studies utilizing HeLa cervical cancer cell lines, the composite nanoparticles are shown to exhibit low dark toxicity and efficient cancer cell‐killing activity upon NIR excitation. Exposure with 134 W cm^?2 of 978 nm light for 45 min resulted in 75% HeLa cell death. This is the first quantification of the cell‐killing capabilities of the UCNP/TPP composite nanoparticles formulated for photodynamic therapy.     

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.     

Biocompatible,Uniform, and Redispersible Mesoporous Silica Nanoparticles for Cancer‐Targeted Drug Delivery In Vivo

Engineering multifunctional nanocarriers for targeted drug delivery shows promising potentials to revolutionize the cancer chemotherapy. Simple methods to optimize physicochemical characteristics and surface composition of the drug nanocarriers need to be developed in order to tackle major challenges for smooth translation of suitable nanocarriers to clinical applications. Here, rational development and utilization of multifunctional mesoporous silica nanoparticles (MSNPs) for targeting MDA‐MB‐231 xenograft model breast cancer in vivo are reported. Uniform and redispersible poly(ethylene glycol)‐incorporated MSNPs with three different sizes (48, 72, 100 nm) are synthesized. They are then functionalized with amino‐β‐cyclodextrin bridged by cleavable disulfide bonds, where amino‐β‐cyclodextrin blocks drugs inside the mesopores. The incorporation of active folate targeting ligand onto 48 nm of multifunctional MSNPs (PEG‐MSNPs48‐CD‐PEG‐FA) leads to improved and selective uptake of the nanoparticles into tumor. Targeted drug delivery capability of PEG‐MSNPs48‐CD‐PEG‐FA is demonstrated by significant inhibition of the tumor growth in mice treated with doxorubicin‐loaded nanoparticles, where doxorubicin is released triggered by intracellular acidic pH and glutathione. Doxorubicin‐loaded PEG‐MSNPs48‐CD‐PEG‐FA exhibits better in vivo therapeutic efficacy as compared with free doxorubicin and non‐targeted nanoparticles. Current study presents successful utilization of multifunctional MSNP‐based drug nanocarriers for targeted cancer therapy in vivo.     

Long‐Circulating Drug‐Dye‐Based Micelles with Ultrahigh pH‐Sensitivity for Deep Tumor Penetration and Superior Chemo‐Photothermal Therapy

Nanocarriers for chemo‐photothermal therapy suffer from insufficient retention at the tumor site and poor penetration into tumor parenchyma. A smart drug‐dye‐based micelle is designed by making the best of the structural features of small‐molecule drugs. P‐DOX is synthesized by conjugating doxorubicin (DOX) with poly(4‐formylphenyl methacrylate‐co‐2‐(diethylamino) ethyl methacrylate)‐b‐polyoligoethyleneglycol methacrylate (P(FPMA‐co‐DEA)‐b‐POEGMA) via imine linkage. Through the π–π stacking interaction, IR780, a near‐infrared fluorescence dye as well as a photothermal agent, is integrated into the micelles (IR780‐PDMs) with the P‐DOX. The IR780‐PDMs show remarkably long blood circulation (t_1/2β = 22.6 h). As a result, a progressive tumor accumulation and retention are presented, which is significant to the sequential drug release. Moreover, when entering into a moderate acidic tumor microenvironment, IR780‐PDMs can dissociate into small‐size conjugates and IR780, which obviously increases the penetration depth of drugs, and then improves the lethality to deep‐seated tumor cells. Owing to the high delivery efficiency and superior chemo‐photothermal therapeutic efficacy of IR780‐PDMs, 97.6% tumor growth in the A549 tumor‐bearing mice is suppressed with a low dose of intravenous injection (DOX, 1.5 mg kg^?1; IR780, 0.8 mg kg^?1). This work presents a brand‐new strategy for long‐acting intensive cancer therapy.     

Polyhedral Oligomeric Silsesquioxanes‐Containing Conjugated Polymer Loaded PLGA Nanoparticles with Trastuzumab (Herceptin) Functionalization for HER2‐Positive Cancer Cell Detection

The synthesis of polyhedral oligomeric silsesquioxanes (POSS)‐containing conjugated polymer (CP) and the polymer loaded poly(lactic‐co‐glycolic‐acid) (PLGA) nanoparticles (NPs) with surface antibody functionalization for human epidermal growth factor receptor 2 (HER2)‐positive cancer cell detection are reported. Due to the steric hindrance of POSS, NPs prepared from POSS‐containing CP show improved photoluminescence quantum yield as compared to that for the corresponding linear CP encapsulated NPs. In addition, the amount of ‐NH₂ groups on NP surface is well‐controlled by changing the molar ratio of poly(lactic‐co‐glycolic‐acid)‐b‐poly(ethylene glycol) (PLGA‐b‐PEG‐NH₂) to PLGA‐OCH₃ during NP formulation. Further conjugation of the NH₂‐functionalized CP NPs with trastuzumab (Herceptin) yields NPs with fine‐tuned protein density. These NPs are able to discriminate SKBR‐3 breast cancer cells from MCF‐7 breast cancer cells and NIH/3T3 fibroblast cells both on substrate and in suspension by taking advantage of the specific binding affinity between trastuzumab and HER2 overexpressed in SKBR‐3 breast cancer cell membrane. The high quantum yield and fine‐tuned surface specific protein functionalization make the POSS‐containing CP loaded NPs a good candidate for targeted biological imaging and detection.     

Cancer Detection: Polyhedral Oligomeric Silsesquioxanes‐Containing Conjugated Polymer Loaded PLGA Nanoparticles with Trastuzumab (Herceptin) Functionalization for HER2‐Positive Cancer Cell Detection (Adv. Funct. Mater. 2/2011)

The synthesis of polyhedral oligomeric silsesquioxanes (POSS)‐containing conjugated polymer (CP) and the polymer loaded poly(lactic‐co‐glycolic‐acid) (PLGA) nanoparticles (NPs) with surface antibody functionalization for human epidermal growth factor receptor 2 (HER2)‐positive cancer cell detection are reported. Due to the steric hindrance of POSS, NPs prepared from POSS‐containing CP show improved photoluminescence quantum yield as compared to that for the corresponding linear CP encapsulated NPs. In addition, the amount of ‐NH₂ groups on NP surface is well‐controlled by changing the molar ratio of poly(lactic‐co‐glycolic‐acid)‐b‐poly(ethylene glycol) (PLGA‐b‐PEG‐NH₂) to PLGA‐OCH₃ during NP formulation. Further conjugation of the NH₂‐functionalized CP NPs with trastuzumab (Herceptin) yields NPs with fine‐tuned protein density. These NPs are able to discriminate SKBR‐3 breast cancer cells from MCF‐7 breast cancer cells and NIH/3T3 fibroblast cells both on substrate and in suspension by taking advantage of the specific binding affinity between trastuzumab and HER2 overexpressed in SKBR‐3 breast cancer cell membrane. The high quantum yield and fine‐tuned surface specific protein functionalization make the POSS‐containing CP loaded NPs a good candidate for targeted biological imaging and detection.     

Ultraeffective Cancer Therapy with an Antimonene‐Based X‐Ray Radiosensitizer

Nanoparticulate chemotherapeutics hold great potential for inducing reactive oxygen species (ROS) overproduction and exerting antihypoxic effects for efficient cancer radiotherapy. However, previous strategies for designing smart radiosensitizers necessitate the multistep incorporation of nanomaterials to achieve valuable radiosensitive outcomes, which causes unpredictable safety issues including poor decomposition and undefined biotransformations. Ultrathin antimonene nanoparticles (AMNPs) are demonstrated as new radiosensitizers that achieve an efficient radiochemotherapeutic effect through the induction of a strong oxidative stress response and their significantly high radiotoxicity in vivo. Analyzing the irradiation process of AMNPs indicates that irradiation accelerates photoelectron generation and the valence transition to toxic Sb₂O₃, leading to cancer cell apoptosis and S‐phase arrest. The tumor regression activity and concealed biotoxicity of the AMNPs in a melanoma mouse model enhance the applicability of antimonene to overcoming radioresistance by increasing ROS generation and normoxia. This new technology can extend the applications of antimonene as an effective radiosensitizer and can promote its clinical translation for tunable and effective radiosensitization in the future.     

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.     

Nonoxidized MXene Quantum Dots Prepared by Microexplosion Method for Cancer Catalytic Therapy

Nanocatalysts based on Fenton or Fenton‐like reactions for amplification of intracellular oxidative stress has become a frontier research area of tumor precise therapy. However, the major translational challenges are low catalytic efficiency, poor biocompatibility, and even potential toxicities. Here, a Ti‐based material with excellent biocompatibility is proposed for cancer treatment. The nonoxidized MXene‐Ti₃C₂T_x quantum dots (NMQDs‐Ti₃C₂T_x) are successfully prepared by a self‐designed microexplosion method. Surprisingly, it has an apparent inhibitory and killing effect on cancer cells, and excellent biocompatibility with normal cells. Moreover, the suppression rate of NMQDs‐Ti₃C₂T_x on xenograft tumor models can reach 91.9% without damaging normal tissues. Mechanistically, the Ti³⁺ of NMQDs‐Ti₃C₂T_x can react with H₂O₂ in the tumor microenvironment and high‐efficiently produce excessive toxic hydroxyl radicals to increase tumor microvascular permeability to synergistically kill cancer cells. This work should pave the way for tumor catalytic therapy applications of Ti‐based material as a promising and safer route.     

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.     

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.     

Multiantigenic Nanoformulations Activate Anticancer Immunity Depending on Size

Nanoparticle‐adjuvanted cancer vaccines are attracting increasing attention because they can induce an effective anticancer immune response. Single‐antigen vaccines are inefficient to inhibit cancer progression due to the heterogeneity of tumors and the antigenicity alteration of tumor‐associated antigens. Therefore, the efficient delivery of multiple antigens to antigen‐presenting cells is an excellent opportunity for strong anticancer immunity. In this study, three immunoadjuvant‐loaded multiantigenic nanoparticles MANPs/R837 with different diameters, i.e., 83, 103, and 122 nm, are prepared through coating of the cancer cell membrane as a source of multiple antigens onto the imiquimod R837‐loaded poly(lactic‐co‐glycolic acid) nanoparticles. The MANP/R837 with a diameter of 83 nm (MANP83/R837) shows the most efficient delivery of the payload to the draining lymph nodes and achieves the best antigen presentation to T lymphocytes. Compared with the other two nanovaccines, MANP83/R837 has a stronger inhibitory effect on tumor growth and metastasis. In the combination therapy with checkpoint blockade therapy using programmed cell death‐1 antibody, MANPs/R837 show effective inhibition against tumor progression, and MANP83/R837 achieves the most exciting effect. Therefore, MANPs/R837, as a promising therapeutic cancer vaccine, demonstrates great prospects in cancer immunotherapy.