On-Demand Autophagy Cascade Amplification Nanoparticles Precisely Enhanced Oxaliplatin-Induced Cancer Immunotherapy

Chemoimmunotherapy-induced antitumor immune response is highly dependent on tumor autophagy. When tumor cells are treated with chemoimmunotherapy, timely overactivated autophagy can not only lead more tumor cells to death, but also participate in the endogenous antigen presentation and immune stimulators secretion of dying cells, thus plays a vital role. However, timely and accurately overactivated tumor autophagy during chemoimmunotherapy is of great difficulty. Here, an on-demand autophagy cascade amplification nanoparticle (ASN) is reported to boost oxaliplatin-induced cancer immunotherapy. ASN is prepared by self-assemble of autophagy-responsible C-TFG micelle and is followed by electrostatic binding of oxaliplatin prodrug (HA-OXA). After entering tumor cells, the HA-OXA shell of ASN first responds to the reduction microenvironment and releases oxaliplatin to trigger tumor immunogenic cell death and mildly stimulates tumor autophagy. Then, the exposed C-TFG micelle can sensitively respond to oxaliplatin-induced autophagy and release a powerful autophagy inducer STF-62247, which precisely transforms autophagy to “overactivated” condition, leading tumor cells to autophagic death and enhance subsequent tumor antigen processing of the dying cells. In CT26 tumor-bearing mice, ASN exhibits optimal immune stimulation and antitumor efficiency due to its on-demand autophagy induction ability.     

Nanodrug Inducing Autophagy Inhibition and Mitochondria Dysfunction for Potentiating Tumor Photo-Immunotherapy

Anticancer immunotherapy is hampered by the poor tumor immunogenicity and immunosuppressive tumor microenvironment (TME). Herein, a liposome nanodrug co-encapsulating doxycycline hydrochloride (Doxy) and chlorin e6 (Ce6) to simultaneously induce autophagy inhibition and mitochondria dysfunction for potentiating tumor photo-immunotherapy is developed. Under near infrared laser irradiation, Ce6 generates cytotoxic reactive oxygen species (ROS) and elicits robust photodynamic therapy (PDT)-induced immunogenic cell death (ICD) for immunosuppressive TME remodeling. In addition, Doxy induced mitochondria dysfunction, which increases ROS generation and enhances PDT to exert more potent killing effect and more powerful ICD. Meanwhile, Doxy increases MHC-I expression on tumor cells surface by efficient autophagy inhibition, leading to more efficient antigen presentation and CTLs recognition to increase tumor immunogenicity. The nanodrugs elicit remarkable antitumor therapy by combining Ce6-mediated PDT and Doxy-induced autophagy inhibition and mitochondria dysfunction. The developed nanodrugs represent a highly efficient strategy for improving cancer immunotherapy.     

PD‐1 Blockade for Improving the Antitumor Efficiency of Polymer–Doxorubicin Nanoprodrug

Chemotherapy is well recognized to induce immune responses during some chemotherapeutic drugs‐mediated tumor eradication. Here, a strategy involving blocking programmed cell death protein 1 (PD‐1) to enhance the chemotherapeutic effect of a doxorubicin nanoprodrug HA‐Psi‐DOX is proposed and the synergetic mechanism between them is further studied. The nanoprodrugs are fabricated by conjugating doxorubicin (DOX) to an anionic polymer hyaluronic acid (HA) via a tumor overexpressed matrix metalloproteinase sensitive peptide (CPLGLAGG) for tumor targeting and enzyme‐activated drug release. Once accumulated at the tumor site, the nanoprodrug can be activated to release antitumor drug by tumor overexpressed MMP‐2. It is found that HA‐Psi‐DOX nanoparticles can kill tumor cells effectively and initiate an antitumor immune response, leading to the upregulation of interferon‐γ. This cytokine promotes the expression of programmed cell death protein‐ligand 1 (PD‐L1) on tumor cells, which will cause immunosuppression after interacting with PD‐1 on the surface of lymphocytes. The results suggest that the therapeutic efficiency of HA‐Psi‐DOX nanoparticles is significantly improved when combined with checkpoint inhibitors anti‐PD‐1 antibody (α‐PD1) due to the neutralization of immunosuppression by blocking the interaction between PD‐L1 and PD‐1. This therapeutic system by combining chemotherapy and immunotherapy further increases the link between conventional tumor therapies and immunotherapy.     

Massively Evoking Immunogenic Cell Death by Focused Mitochondrial Oxidative Stress using an AIE Luminogen with a Twisted Molecular Structure

Immunogenic cell death (ICD) provides momentous theoretical principle for modern cancer immunotherapy. However, the currently available ICD inducers are still very limited and photosensitizer‐based ones can hardly induce sufficient ICD to achieve satisfactory cancer immunotherapy by themselves. Herein, an organic photosensitizer (named TPE‐DPA‐TCyP) with a twisted molecular structure, strong aggregation‐induced emission activity, and specific ability is reported for effectively inducing focused mitochondrial oxidative stress of cancer cells, which can serve as a much superior ICD inducer to the popularly used ones, including chlorin e6 (Ce6), pheophorbide A, and oxaliplatin. Furthermore, more effective in vivo ICD immunogenicity of TPE‐DPA‐TCyP than Ce6 is also demonstrated using a prophylactic tumor vaccination model. The underlying mechanism of the effectiveness and robustness of TPE‐DPA‐TCyP in inducing antitumor immunity and immune‐memory effect in vivo is verified by immune cell analyses. This study thus reveals that inducing focused mitochondrial oxidative stress is a highly effective strategy to evoke abundant and large‐scale ICD.     

Tumor-Activated Size-Enlargeable Bioinspired Lipoproteins Access Cancer Cells in Tumor to Elicit Anti-Tumor Immune Responses

The limited lymphocytes infiltration and immunosuppression in tumor are the major challenges of cancer immunotherapy. The use of immunogenic cell death (ICD)-inducing agents has potential to potentiate antitumor immune responses, but is tremendously hampered by the poor delivery efficiency. Herein, a tumor-activated size-enlargeable bioinspired lipoprotein of oxaliplatin (TA-OBL) is designed to access cancer cells and boost the ICD-induced antitumor immunity for synergizing immune-checkpoint blockades (ICBs)-mediated immunotherapy. TA-OBL is constructed by integrating a legumain-sensitive melittin conjugate for improving intratumoral permeation and cancer cell accessibility, a pH-sensitive phospholipid for triggering size-enlargement and drug release in intracellular acidic environments, a nitroreductase-sensitive hydrophobic oxaliplatin prodrug (N-OXP) for eliciting antitumor immunity into the bioinspired nano-sized lipoprotein system. TA-OBL treatment produced robust antitumor immune responses and its combination with ICBs demonstrates strong therapeutic benefits with delayed tumor growth and extended survival rate, making it a promising delivery nanoplatform to elicit antitumor immunity for cancer immunotherapy.     

NIR-II Imaging-Guided Mitochondrial-Targeting Organic Nanoparticles for Multimodal Synergistic Tumor Therapy

Effectively interfering energy metabolism in tumor cells and simultaneously activating the in vivo immune system to perform immune attacks are meaningful for tumor treatment. However, precisely targeted therapy is still a huge challenge. Herein, a mitochondrial-targeting phototheranostic system, FE-T nanoparticles (FE-T NPs) are developed to damage mitochondria in tumor cells and change the tumor immunosuppressive microenvironment. FE-T NPs are engineered by encapsulating the near-infrared (NIR) absorbed photosensitizer IR-FE-TPP within amphiphilic copolymer DSPE-SS-PEG-COOH for high-performing with simultaneous mitochondrial-targeting, near-infrared II (NIR-II) fluorescence imaging, and synchronous photothermal therapy (PTT) /photodynamic therapy (PDT) /immune therapy (IMT). In tumor treatment, the disulfide in the copolymer can be cleaved by excess intracellular glutathione (GSH) to release IR-FE-TPP and accumulate in mitochondria. After 808 nm irradiation, the mitochondrial localization of FE-T NPs generated reactive oxygen species (ROS), and hyperthermia, leading to mitochondrial dysfunction, photoinductive apoptosis, and immunogenic cell death (ICD). Notably, in situ enhanced PDT/PTT in vivo via mitochondrial-targeting with FE-T NPs boosts highly efficient ICD toward excellent antitumor immune response. FE-T NPs provide an effective mitochondrial-targeting phototheranostic nanoplatform for imaging-guided tumor therapy.     

Carbon nanotubes conjugated to tumor lysate protein enhance the efficacy of an antitumor immunotherapy

The biomedical applications of carbon nanotubes (CNTs) have attracted deep interest in recent years. Antitumor immunotherapy has the potential to improve the prognosis of cancer treatment but the efficacy of current immunotherapy generally needs further improvement. Multi-walled CNTs conjugated to tumor lysate protein are investigated as to whether they would enhance the efficacy of an immunotherapy employing a tumor-cell vaccine in a mouse model bearing the H22 liver cancer. The tumor cure rate is found to be markedly improved by CNTs conjugated to tumor lysate protein. The cellular antitumor immune reaction is also enhanced. Moreover, the observed antitumor immune response is relatively specific against the tumor intended for treatment. These findings suggest that CNTs may have a prospective role in the development of new antitumor immunotherapies.     

Binary Cooperative Prodrug Nanoparticles Improve Immunotherapy by Synergistically Modulating Immune Tumor Microenvironment

Checkpoint blockade immunotherapy is promising for clinical treatment of various malignant tumors. However, checkpoint blockade immunotherapy suffers from a low response rate due to insufficient tumor immunogenicity and the immunosuppressive tumor microenvironment (ITM). In this study, a tumor‐microenvironment‐activatable binary cooperative prodrug nanoparticle (BCPN) is rationally designed to improve immunotherapy by synergistically modulating the immune tumor microenvironment. BCPN is purely constructed from a tumor acidity and reduction dual‐responsive oxaliplatin (OXA) prodrug for triggering immunogenic cell death (ICD) and eliciting antitumor immunity, and a reduction‐activatable homodimer of NLG919 for inactivating indoleamine 2,3‐dioxygenase 1, which is a key regulator for ITM. Upon tumor‐acidity‐triggered cleavage of the poly(ethylene glycol) shell, PN shows negative to positive charge switch for enhanced tumor accumulation and deep penetration. OXA and NLG919 are then activated in the tumor cells via glutathione‐mediated reduction. It is demonstrate that activated OXA promotes intratumoral accumulation of cytotoxic T lymphocytes by triggering ICD of cancer cells. Meanwhile, NLG919 downregulates IDO‐1‐mediated immunosuppression and suppresses regulatory T cells. Most importantly, PN shows much higher efficiency than free OXA or the combination of free OXA and NLG919 to regress tumor growth and prevent metastasis of mouse models of both breast and colorectal cancer.     

Intermittent Fasting Primes the Tumor Microenvironment and Improves Nanomedicine Delivery in Hepatocellular Carcinoma

Fasting has many health benefits, including reduced chemotherapy toxicity and improved efficacy. It is unclear how fasting affects the tumor microenvironment (TME) and tumor-targeted drug delivery. Here the effects of intermittent (IF) and short-term (STF) fasting are investigated on tumor growth, TME composition, and liposome delivery in allogeneic hepatocellular carcinoma (HCC) mouse models. To this end, mice are inoculated either subcutaneously or intrahepatically with Hep-55.1C cells and subjected to IF for 24 d or to STF for 1 d. IF but not STF significantly slows down tumor growth. IF increases tumor vascularization and decreases collagen density, resulting in improved liposome delivery. In vitro, fasting furthermore promotes the tumor cell uptake of liposomes. These results demonstrate that IF shapes the TME in HCC towards enhanced drug delivery. Finally, when combining IF with liposomal doxorubicin treatment, the antitumor efficacy of nanochemotherapy is found to be increased, while systemic side effects are reduced. Altogether, these findings exemplify that the beneficial effects of fasting on anticancer therapy outcomes go beyond modulating metabolism at the molecular level.     

MUC1 aptamer-conjugated mesoporous silica nanoparticles effectively target breast cancer cells

In the present study, we developed aptamer (Apt) conjugated mesoporous silica nanoparticles (MSNs) for specific delivery of epirubicin (EPI) to breast cancer cells. MSNs were synthesized and functionalized with 3-mercaptopropyltrimethoxysilane (3-MPTMS), followed by MUC1 aptamer conjugation through disulfide bonds. The nanoparticles were analyzed by transmission electron microscopy (TEM), particle size analyzer, zeta potential, elemental analysis (CHNS), aptamer conjugation efficiency, drug loading efficiency, and drug release profile. Cell uptake and in vitro cytotoxicity of different formulations were performed. The results of MSNs characterization confirmed spherical nanoparticles with thiol functional groups. Particle size of obtained nanoparticles was 163?nm in deionized water. After conjugation of MUC1 aptamer and EPI loading (MSN-MUC1-EPI), particle size increased to 258?nm. The aptamer conjugation to MSNs with disulfide bonds were confirmed using gel retardation assay. Cellular uptake studies revealed better cell uptake of MSN-MUC1-EPI compared to MSN-EPI. Moreover, cytotoxicity study results in MCF7 cell lines showed improved cytotoxicity of MSN-MUC1-EPI in comparison with MSN-EPI or EPI at the same concentration of drug. These results exhibited that MSN-MUC1-EPI has the potential for targeted drug delivery into MUC1 positive breast cancer cells to improve drug efficacy and alleviate side effects.     

Selenium-Containing Nanoparticles Combine the NK Cells Mediated Immunotherapy with Radiotherapy and Chemotherapy

Considering the limited clinical benefits of individual approaches against malignancy, natural killer (NK) cell-mediated immunotherapy is increasingly utilized in combination with radiotherapy and target therapeutics. However, the interplay of targeted agents, immunotherapy, and radiotherapy is complex. An improved understanding of the effect of chemotherapy or radiotherapy on specific molecular pathways in immune cells would help to optimize the synergistic antitumor efficiency. In this study, the selenium-containing nanoparticles (NPs) could deliver the chemotherapeutic drug doxorubicin (DOX) to tumor sites by systemic administration. Radiation stimuli facilitate DOX release and enhance chemotherapy efficiency. Moreover, radiation could oxidize diselenide-containing NPs to seleninic acid, which have both synergistic antitumor effect and immunomodulatory activity through enhancing NK cells function. These results indicate that the selenium-containing NPs would be a potential approach to achieve simultaneous treatments of immunotherapy, chemotherapy, and radiotherapy by a simple but effective method.     

A Dual Immunotherapy Nanoparticle Improves T‐Cell Activation and Cancer Immunotherapy

Combination immunotherapy has recently emerged as a powerful cancer treatment strategy. A promising treatment approach utilizes coadministration of antagonistic antibodies to block checkpoint inhibitor receptors, such as antiprogrammed cell death‐1 (aPD1), alongside agonistic antibodies to activate costimulatory receptors, such as antitumor necrosis factor receptor superfamily member 4 (aOX40). Optimal T‐cell activation is achieved when both immunomodulatory agents simultaneously engage T‐cells and promote synergistic proactivation signaling. However, standard administration of these therapeutics as free antibodies results in suboptimal T‐cell binding events, with only a subset of the T‐cells binding to both aPD1 and aOX40. Here, it is shown that precise spatiotemporal codelivery of aPD1 and aOX40 using nanoparticles (NP) (dual immunotherapy nanoparticles, DINP) results in improved T‐cell activation, enhanced therapeutic efficacy, and increased immunological memory. It is demonstrated that DINP elicits higher rates of T‐cell activation in vitro than free antibodies. Importantly, it is demonstrated in two tumor models that combination immunotherapy administered in the form of DINP is more effective than the same regimen administered as free antibodies. This work demonstrates a novel strategy to improve combination immunotherapy using nanotechnology.     

Cascade Immune Activation of Self-Delivery Biomedicine for Photodynamic Immunotherapy Against Metastatic Tumor

Photodynamic therapy (PDT) can generate reactive oxygen species (ROS) to cause cell apoptosis and induce immunogenic cell death (ICD) to activate immune response, becoming a promising antitumor modality. However, the overexpressions of indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand 1 (PD-L1) on tumor cells would reduce cytotoxic T cells infiltration and inhibit the immune activation. In this paper, a simple but effective nanosystem is developed to solve these issues for enhanced photodynamic immunotherapy. Specifically, it has been constructed a self-delivery biomedicine (CeNB) based on photosensitizer chlorine e6 (Ce6), IDO inhibitor (NLG919), and PD1/PDL1 blocker (BMS-1) without the need for extra excipients. Of note, CeNB possesses fairly high drug content (nearly 100%), favorable stability, and uniform morphology. More importantly, CeNB-mediated IDO inhibition and PD1/PDL1 blockade greatly improve the immunosuppressive tumor microenvironments to promote immune activation. The PDT of CeNB not only inhibits tumor proliferation but also induces ICD response to activate immunological cascade. Ultimately, self-delivery CeNB tremendously suppresses the tumor growth and metastasis while leads to a minimized side effect. Such simple and effective antitumor strategy overcomes the therapeutic resistance against PDT-initiated immunotherapy, suggesting a potential for metastatic tumor treatment in clinic.     

Tumor Microenvironment‐Activatable Prodrug Vesicles for Nanoenabled Cancer Chemoimmunotherapy Combining Immunogenic Cell Death Induction and CD47 Blockade

Chemoimmunotherapy is reported to activate a robust T cell antitumor immune response by triggering immunogenic cell death (ICD), which has initiated a number of clinical trials. However, current chemoimmunotherapy is restricted to a small fraction of patients due to low drug delivery efficacy and immunosuppression within the tumor microenvironment. A tumor microenvironment‐activatable prodrug vesicle for cancer chemoimmunotherapy using ICD is herein reported. The prodrug vesicles are engineered by integrating an oxaliplatin (OXA) prodrug and PEGylated photosensitizer (PS) into a single nanoplatform, which show tumor‐specific accumulation, activation, and deep penetration in response to the tumoral acidic and enzymatic microenvironment. It is demonstrated that codelivery of OXA prodrug and PS can trigger ICD of the tumor cells by immunogenic cells killing. The combination of prodrug vesicle‐induced ICD with Î ± CD47‐mediated CD47 blockade further facilitates dendritic cell (DC) maturation, promotes antigen presentation by DCs, and eventually propagates the antitumor immunity of ICD. CD47 blockade and ICD induction efficiently inhibit the growth of both primary and abscopal tumors, suppress tumor metastasis, and prevent tumor recurrence. Collectively, these results imply that boosting antitumor immunity using ICD induction and suppressing tumor immune evasion via CD47 blockade might be promising for improved cancer chemoimmunotherapy.     

Polysaccharide-Based Stimulus-Responsive Nanomedicines for Combination Cancer Immunotherapy

Cancer immunotherapy is a promising antitumor approach, whereas nontherapeutic side effects, tumor microenvironment (TME) intricacy, and low tumor immunogenicity limit its therapeutic efficacy. In recent years, combination immunotherapy with other therapies has been proven to considerably increase antitumor efficacy. However, achieving codelivery of the drugs to the tumor site remains a major challenge. Stimulus-responsive nanodelivery systems show controlled drug delivery and precise drug release. Polysaccharides, a family of potential biomaterials, are widely used in the development of stimulus-responsive nanomedicines due to their unique physicochemical properties, biocompatibility, and modifiability. Here, the antitumor activity of polysaccharides and several combined immunotherapy strategies (e.g., immunotherapy combined with chemotherapy, photodynamic therapy, or photothermal therapy) are summarized. More importantly, the recent progress of polysaccharide-based stimulus-responsive nanomedicines for combination cancer immunotherapy is discussed, with the focus on construction of nanomedicine, targeted delivery, drug release, and enhanced antitumor effects. Finally, the limitations and application prospects of this new field are discussed.     

Codelivery of Anti‐PD‐1 Antibody and Paclitaxel with Matrix Metalloproteinase and pH Dual‐Sensitive Micelles for Enhanced Tumor Chemoimmunotherapy

Immune checkpoint blockade (ICB) is demonstrating great potential in cancer immunotherapy nowadays. Yet, the low response rate to ICB remains an urgent challenge for tumor immunotherapy. A pH and matrix metalloproteinase dual‐sensitive micellar nanocarrier showing spatio‐temporally controlled release of anti‐PD‐1 antibody (aPD‐1) and paclitaxel (PTX) in solid tumors is prepared to realize synergistic cancer chemoimmunotherapy. Antitumor immunity can be activated by PTX‐induced immunogenic cell death (ICD), while aPD‐1 blocks the PD‐1/PD‐L1 axis to suppress the immune escape due to PTX‐induced PD‐L1 up‐regulation, thus resulting in a synergistic antitumor chemoimmunotherapy. Through decoration with a sheddable polyethylene glycol (PEG) shell, the nanodrug may better accumulate in tumors to boost the synergistic antitumor treatment in a mouse melanoma model. The present study demonstrates a potent antitumor chemoimmunotherapy utilizing tumor microenvironment‐sensitive micelles bearing a sheddable PEG layer to mediate site‐specific sequential release of aPD‐1 and PTX.     

Sequentially Responsive Shell‐Stacked Nanoparticles for Deep Penetration into Solid Tumors

Nanomedicine to overcome both systemic and tumor tissue barriers ideally should have a transformable size and surface, maintaining a certain size and negative surface charge for prolonged circulation, while reducing to a smaller size and switching to a positive surface charge for efficient penetration to and retention in the interstitial space throughout the tumor tissue. However, the design of such size and charge dual‐transformable nanomedicine is rarely reported. Here, the design of a shell‐stacked nanoparticle (SNP) is reported, which can undergo remarkable size reduction from about 145 to 40 nm, and surface charge reversal from ?7.4 to 8.2 mV at acidic tumor tissue, for enhanced tumor penetration and uptake by cells in deep tumor tissue. The disulfide‐cross‐linked core maintains the stability of the particle and prevents undesired premature drug release until the shedding of the shell, which accelerates the cleavage of more exposed disulfide bond sand intracellular drug release. SNP penetrates about 1 mm into xenografted A549 lung carcinoma, which is about four times penetration depth of the nontransformable one. The doxorubicin (DOX)‐loaded SNP (SNP/DOX) shows significant antitumor efficacy and nearly eradicates the tumor, substantiating the importance of the design of size and charge dual‐transformable nanomedicine.     

Platelet Membrane‐Camouflaged Magnetic Nanoparticles for Ferroptosis‐Enhanced Cancer Immunotherapy

Although cancer immunotherapy has emerged as a tremendously promising cancer therapy method, it remains effective only for several cancers. Photoimmunotherapy (e.g., photodynamic/photothermal therapy) could synergistically enhance the immune response of immunotherapy. However, excessively generated immunogenicity will cause serious inflammatory response syndrome. Herein, biomimetic magnetic nanoparticles, Fe₃O₄‐SAS @ PLT, are reported as a novel approach to sensitize effective ferroptosis and generate mild immunogenicity, enhancing the response rate of non‐inflamed tumors for cancer immunotherapy. Fe₃O₄‐SAS@PLT are built from sulfasalazine (SAS)‐loaded mesoporous magnetic nanoparticles (Fe₃O₄) and platelet (PLT) membrane camouflage and triggered a ferroptotic cell death via inhibiting the glutamate‐cystine antiporter system X_c^? pathway. Fe₃O₄‐SAS @ PLT‐mediated ferroptosis significantly improves the efficacy of programmed cell death 1 immune checkpoint blockade therapy and achieves a continuous tumor elimination in a mouse model of 4T1 metastatic tumors. Proteomics studies reveal that Fe₃O₄‐SAS @ PLT‐mediated ferroptosis could not only induce tumor‐specific immune response but also efficiently repolarize macrophages from immunosuppressive M2 phenotype to antitumor M1 phenotype. Therefore, the concomitant of Fe₃O₄‐SAS @ PLT‐mediated ferroptosis with immunotherapy are expected to provide great potential in the clinical treatment of tumor metastasis.     

Tumor‐Targeted Drug and CpG Delivery System for Phototherapy and Docetaxel‐Enhanced Immunotherapy with Polarization toward M1‐Type Macrophages on Triple Negative Breast Cancers

Cancer immunotherapy has achieved promising clinical responses in recent years owing to the potential of controlling metastatic disease. However, there is a limited research to prove the superior therapeutic efficacy of immunotherapy on breast cancer compared with melanoma and non‐small‐cell lung cancer because of its limited expression of PD‐L1, low infiltration of cytotoxic T lymphocytes (CTLs), and high level of myeloid‐derived suppressor cells (MDSCs). Herein, a multifunctional nanoplatform (FA‐CuS/DTX@PEI‐PpIX‐CpG nanocomposites, denoted as FA‐CD@PP‐CpG) for synergistic phototherapy (photodynamic therapy (PDT), photothermal therapy (PTT) included) and docetaxel (DTX)‐enhanced immunotherapy is successfully developed. The nanocomposites exhibit excellent PDT efficacy and photothermal conversion capability under 650 and 808 nm irradiation, respectively. More significantly, FA‐CD@PP‐CpG with no obvious side effects can remarkably inhibit the tumor growth in vivo based on a 4T1‐tumor‐bearing mice modal. A low dosage of loaded DTX in FA‐CD@PP‐CpG can promote infiltration of CTLs to improve efficacy of anti‐PD‐L1 antibody (aPD‐L1), suppress MDSCs, and effectively polarize MDSCs toward M1 phenotype to reduce tumor burden, further to enhance the antitumor efficacy. Taken together, FA‐CD@PP‐CpG nanocomposites offer an efficient synergistic therapeutic modality in docetaxel‐enhanced immunotherapy for clinical application of breast cancer.     

Facile Fabrication of Tumor Redox‐Sensitive Nanoassemblies of Small‐Molecule Oleate Prodrug as Potent Chemotherapeutic Nanomedicine

The conjugate of paclitaxel (PTX) and docosahexaenoic acid has entered into clinical trials. However, the most recent clinical outcomes fell short of expectations, due to the extremely slow drug release from the hydrophobic conjugates. Herein, a novel prodrug‐based nanoplatform self‐assembled by the disulfide bond linked conjugates of PTX and oleic acid for rapid and differential release of PTX in tumor cells is reported. This redox‐responsive prodrug‐nanosystem demonstrates multiple therapeutic advantages, including one‐step facile fabrication, high drug‐loading efficiency (56%, w/w), on‐demand drug release responding to redox stimuli, as well as favorable cellular uptake and biodistribution. These advantages result in significantly enhanced antitumor efficacy in vivo, with the tumor almost completely disappearing in mice. Such a uniquely engineered prodrug‐nanosystem has great potential to be used as potent chemotherapeutic nanomedicine in clinical cancer therapy.