Genetically engineered nanomodulators elicit potent immunity against cancer stem cells by checkpoint blockade and hypoxia relief.

Rapid development of checkpoint inhibitors has provided significant breakthroughs for cancer stem cell (CSC) therapy, while the therapeutic efficacy is restricted by hypoxia-mediated tumor immune evasion, especially hypoxia-induced CD47 overexpression in CSCs. Herein, we developed a genetically engineered CSC membrane-coated hollow manganese dioxide (hMnO2@gCMs) to elicit robust antitumor immunity by blocking CD47 and alleviating hypoxia to ultimately achieve the eradication of CSCs. The hMnO2 core effectively alleviated tumor hypoxia by inducing decomposition of tumor endogenous H2O2, thus suppressing the CSCs and reducing the expression of CD47. Cooperating with hypoxia relief-induced downregulation of CD47, the overexpressed SIRPα on gCM shell efficiently blocked the CD47-SIRPα "don't eat me" pathway, synergistically eliciting robust antitumor-mediated immune responses. In a B16F10-CSC bearing melanoma mouse model, the hMnO2@gCMs showed an enhanced therapeutic effect in eradicating CSCs and inhibiting tumor growth. Our work presents a simple, safe, and robust platform for CSC eradication and cancer immunotherapy.

Genetically Edited Cascade Nanozymes for Cancer Immunotherapy.

Immune checkpoint blockade (ICB) has brought tremendous clinical progress, but its therapeutic outcome can be limited due to insufficient activation of dendritic cells (DCs) and insufficient infiltration of cytotoxic T lymphocytes (CTLs). Evoking immunogenic cell death (ICD) is one promising strategy to promote DC maturation and elicit T-cell immunity, whereas low levels of ICD induction of solid tumors restrict durable antitumor efficacy. Herein, we report a genetically edited cell membrane-coated cascade nanozyme (gCM@MnAu) for enhanced cancer immunotherapy by inducing ICD and activating the stimulator of the interferon genes (STING) pathway. In the tumor microenvironment (TME), the gCM@MnAu initiates a cascade reaction and generates abundant cytotoxic hydroxyl (•OH), resulting in improved chemodynamic therapy (CDT) and boosted ICD activation. In addition, released Mn2+ during the cascade reaction activates the STING pathway and further promotes the DC maturation. More importantly, activated immunogenicity in the TME significantly improves gCM-mediated PD-1/PD-L1 checkpoint blockade therapy by eliciting systemic antitumor responses. In breast cancer subcutaneous and lung metastasis models, the gCM@MnAu showed synergistically enhanced therapeutic effects and significantly prolonged the survival of mice. This work develops a genetically edited nanozyme-based therapeutic strategy to improve DC-mediated cross-priming of T cells against poorly immunogenic solid tumors.

Tea polyphenol-engineered hybrid cellular nanovesicles for cancer immunotherapy and androgen deprivation therapy.

Androgen deprivation therapy (ADT) is a crucial and effective strategy for prostate cancer, while systemic administration may cause profound side effects on normal tissues. More importantly, the ADT can easily lead to resistance by involving the activation of NF-κB signaling pathway and high infiltration of M2 macrophages in tumor microenvironment (TME). Herein, we developed a biomimetic nanotherapeutic platform by deriving cell membrane nanovesicles from cancer cells and probiotics to yield the hybrid cellular nanovesicles (hNVs), loading flutamide (Flu) into the resulting hNVs, and finally modifying the hNVs@Flu with Epigallocatechin-3-gallate (EGCG). In this nanotherapeutic platform, the hNVs significantly improved the accumulation of hNVs@Flu-EGCG in tumor sites and reprogramed immunosuppressive M2 macrophages into antitumorigenic M1 macrophages, the Flu acted on androgen receptors and inhibited tumor proliferation, and the EGCG promoted apoptosis of prostate cancer cells by inhibiting the NF-κB pathway, thus synergistically stimulating the antitumor immunity and reducing the side effects and resistance of ADT. In a prostate cancer mouse model, the hNVs@Flu-EGCG significantly extended the lifespan of mice with tumors and led to an 81.78% reduction in tumor growth compared with the untreated group. Overall, the hNVs@Flu-EGCG are safe, modifiable, and effective, thus offering a promising platform for effective therapeutics of prostate cancer.

Hybrid Cellular Nanovesicles Block PD-L1 Signal and Repolarize M2 Macrophages for Cancer Immunotherapy.

The PD1/PD-L1 immune checkpoint blocking is a promising therapy, while immunosuppressive tumor microenvironment (TME) and poor tumor penetration of therapeutic antibodies limit its efficacy. Repolarization of tumor-associated macrophages (TAMs) offers a potential method to ameliorate immunosuppression of TME and further boost T cell antitumor immunity. Herein, hybrid cell membrane biomimetic nanovesicles (hNVs) are developed by fusing M1 macrophage-derived nanovesicles (M1-NVs) and PD1-overexpressed tumor cell-derived nanovesicles (PD1-NVs) to improve cancer immunotherapy. The M1-NVs promote the transformation of M2-like TAMs to M1-like phenotype and further increase the release of pro-inflammatory cytokines, resulting in improved immunosuppressive TME. Concurrently, the PD1-NVs block PD1/PD-L1 pathway, which boosts cancer immunotherapy when combined with M1-NVs. In a breast cancer mouse model, the hNVs efficiently accumulate at the tumor site after intravenous injection and significantly inhibit the tumor growth. Mechanically, the M1 macrophages and CD8+ T lymphocytes in TME increase by twofold after the treatment, indicating effective immune activation. These results suggest the hNVs as a promising strategy to integrate TME improvement with PD1/PD-L1 blockade for cancer immunotherapy.

Genetically Engineered Cytomembrane Nanovaccines for Cancer Immunotherapy.

Cancer nanovaccines have attracted widespread attention by inducing potent cytotoxic T cell responses to improve immune checkpoint blockade (ICB) therapy, while the lack of co-stimulatory molecules limits their clinical applications. Here, a genetically engineered cancer cytomembrane nanovaccine is reported that simultaneously overexpresses co-stimulatory molecule CD40L and immune checkpoint inhibitor PD1 to elicit robust antitumor immunity for cancer immunotherapy. The CD40L and tumor antigens inherited from cancer cytomembranes effectively stimulate dendritic cell (DC)-mediated immune activation of cytotoxic T cells, while the PD1 on cancer cytomembranes significantly blocks PD1/PD-L1 signaling pathway, synergistically stimulating antitumor immune responses. Benefiting from the targeting ability of cancer cytomembranes, this nanovaccines formula shows an enhanced lymph node trafficking and retention. Compared with original cancer cytomembranes, this genetically engineered nanovaccine induces twofold DC maturation and shows satisfactory precaution efficacy in a breast tumor mouse model. This genetically engineered cytomembrane nanovaccine offers a simple, safe, and robust strategy by incorporating cytomembrane components and co-stimulatory molecules for enhanced cancer immunotherapy.

Triple Hybrid Cellular Nanovesicles Promote Cardiac Repair after Ischemic Reperfusion.

The management of myocardial ischemia/reperfusion (I/R) damage in the context of reperfusion treatment remains a significant hurdle in the field of cardiovascular disorders. The injured lesions exhibit distinctive features, including abnormal accumulation of necrotic cells and subsequent inflammatory response, which further exacerbates the impairment of cardiac function. Here, we report genetically engineered hybrid nanovesicles (hNVs), which contain cell-derived nanovesicles overexpressing high-affinity SIRPα variants (SαV-NVs), exosomes (EXOs) derived from human mesenchymal stem cells (MSCs), and platelet-derived nanovesicles (PLT-NVs), to facilitate the necrotic cell clearance and inhibit the inflammatory responses. Mechanistically, the presence of SαV-NVs suppresses the CD47-SIRPα interaction, leading to the promotion of the macrophage phagocytosis of dead cells, while the component of EXOs aids in alleviating inflammatory responses. Moreover, the PLT-NVs endow hNVs with the capacity to evade immune surveillance and selectively target the infarcted area. In I/R mouse models, coadministration of SαV-NVs and EXOs showed a notable synergistic effect, leading to a significant enhancement in the left ventricular ejection fraction (LVEF) on day 21. These findings highlight that the hNVs possess the ability to alleviate myocardial inflammation, minimize infarct size, and improve cardiac function in I/R models, offering a simple, safe, and robust strategy in boosting cardiac repair after I/R.

Tumor Microenvironment-Responsive Nanoparticles Amplifying STING Signaling Pathway for Cancer Immunotherapy.

Insufficient activation of the stimulator of interferon genes (STING) signaling pathway and profoundly immunosuppressive microenvironment largely limits the effect of cancer immunotherapy. Herein, tumor microenvironment (TME)-responsive nanoparticles (PMM NPs) are exploited that simultaneously harness STING and Toll-like receptor 4 (TLR4) to augment STING activation via TLR4-mediated nuclear factor-kappa B signaling pathway stimulation, leading to the increased secretion of type I interferons (i.e., 4.0-fold enhancement of IFN-ß) and pro-inflammatory cytokines to promote a specific T cell immune response. Moreover, PMM NPs relieve the immunosuppression of the TME by decreasing the percentage of regulatory T cells, and polarizing M2 macrophages to the M1 type, thus creating an immune-supportive TME to unleash a cascade adaptive immune response. Combined with an anti-PD-1 antibody, synergistic efficacy is achieved in both inflamed colorectal cancer and noninflamed metastatic breast tumor models. Moreover, rechallenging tumor-free animals with homotypic cells induced complete tumor rejection, indicating the generation of systemic antitumor memory. These TME-responsive nanoparticles may open a new avenue to achieve the spatiotemporal orchestration of STING activation, providing a promising clinical candidate for next-generation cancer immunotherapy.

In situ formed scaffold with royal jelly-derived extracellular vesicles for wound healing.

Background: Safe and effective wound healing can be a major clinical challenge. Inflammation and vascular impairment are two main causes of inadequate wound healing. Methods: Here, we developed a versatile hydrogel wound dressing, comprising a straightforward physical mixture of royal jelly-derived extracellular vesicles (RJ-EVs) and methacrylic anhydride modified sericin (SerMA), to accelerate wound healing by inhibiting inflammation and promoting vascular reparation. Results: The RJ-EVs showed satisfactory anti-inflammatory and antioxidant effects, and significantly promoted L929 cell proliferation and migration in vitro. Meanwhile, the photocrosslinked SerMA hydrogel with its porous interior structure and high fluidity made it a good candidate for wound dressing. The RJ-EVs can be gradually released from the SerMA hydrogel at the wound site, ensuring the restorative effect of RJ-EVs. In a full-thickness skin defect model, the SerMA/RJ-EVs hydrogel dressing accelerated wound healing with a healing rate of 96.8% by improving cell proliferation and angiogenesis. The RNA sequencing results further revealed that the SerMA/RJ-EVs hydrogel dressing was involved in inflammatory damage repair-related pathways including recombinational repair, epidermis development, and Wnt signaling. Conclusion: This SerMA/RJ-EVs hydrogel dressing offers a simple, safe and robust strategy for modulating inflammation and vascular impairment for accelerated wound healing.

Inhalation delivery of dexamethasone with iSEND nanoparticles attenuates the COVID-19 cytokine storm in mice and nonhuman primates.

Dexamethasone (DEX) is the first drug to show life-saving efficacy in patients with severe coronavirus disease 2019 (COVID-19), while DEX is associated with serious adverse effects. Here, we report an inhaled, Self-immunoregulatory, Extracellular Nanovesicle-based Delivery (iSEND) system by engineering neutrophil nanovesicles with cholesterols to deliver DEX for enhanced treatment of COVID-19. Relying on surface chemokine and cytokine receptors, the iSEND showed improved targeting to macrophages and neutralized broad-spectrum cytokines. The nanoDEX, made by encapsulating DEX with the iSEND, efficiently promoted the anti-inflammation effect of DEX in an acute pneumonia mouse model and suppressed DEX-induced bone density reduction in an osteoporosis rat model. Relative to an intravenous administration of DEX at 0.1 milligram per kilogram, a 10-fold lower dose of nanoDEX administered by inhalation produced even better effects against lung inflammation and injury in severe acute respiratory syndrome coronavirus 2-challenged nonhuman primates. Our work presents a safe and robust inhalation delivery platform for COVID-19 and other respiratory diseases.

Application of CT functional imaging in the assessment of chemotherapy efficacy in lung cancer.

In this research, we aim to investigate the feasibility of a one-stop CT energy spectrum perfusion imaging technique for chemotherapy efficacy assessment of lung cancer patients by obtaining both functional imaging parameters of energy spectrum and perfusion in one scan. From November 2018 to February 2020, a group of 23 patients with pathologically confirmed lung cancer were chosen to undergo CT energy spectrum scans both before and after treatment. The post-treatment CT perfusion data was acquired one week after the second conventional chemotherapy session. Out of the 23 patients, 15 were in the chemotherapy effective group and the remaining 8 were in the ineffective group. The reason for this group was according to recist criteria. Arterial phase iodine concentration (icap) and intravenous phase iodine concentration (icpp) of the lesions were measured, and standardized iodine base values (nic) were calculated. The maximum diameter of the tumor before and after treatment was compared to the perfusion parameters and energy spectrum parameters before and after chemotherapy in the effective group and the invalid group was compared by two tests that p<0.05. The differences between the maximum diameter of the tumor before and after chemotherapy. 2 of the 15 patients in the effective group had liquefied necrotic areas in their lesions. One-stop ct energy-spectrum perfusion imaging can show the disease progression from a functional perspective and assess the efficacy early according to the changes in perfusion parameters and energy-spectrum parameters after lung cancer treatment.

Boosting Checkpoint Immunotherapy with Biomaterials.

The immune checkpoint blockade (ICB) therapy has revolutionized the field of cancer treatment, while low response rates and systemic toxicity limit its clinical outcomes. With the rapid advances in nanotechnology and materials science, various types of biomaterials have been developed to maximize therapeutic efficacy while minimizing side effects by increasing tumor antigenicity, reversing immunosuppressive microenvironment, amplifying antitumor immune response, and reducing extratumoral distribution of checkpoint inhibitors as well as enhancing their retention within target sites. In this review, we reviewed current design strategies for different types of biomaterials to augment ICB therapy effectively and then discussed present representative biomaterial-assisted immune modulation and targeted delivery of checkpoint inhibitors to boost ICB therapy. Current challenges and future development prospects for expanding the ICB with biomaterials were also summarized. We anticipate this review will be helpful for developing emerging biomaterials for ICB therapy and promoting the clinical application of ICB therapy.

Organic-Inorganic Porphyrinoid Frameworks for Biomolecule Sensing.

Porphyrinoids and their analogous compounds play an important role in biosensing applications on account of their unique and versatile catalytic, coordination, photophysical, and electrochemical properties. Their remarkable arrays of properties can be finely tuned by synthetically modifying the porphyrinoid ring and varying the various structural parameters such as peripheral functionalization, metal coordination, and covalent or physical conjugation with other organic or inorganic scaffolds such as nanoparticles, metal-organic frameworks, and polymers. Porphyrinoids and their organic-inorganic conjugates are not only used as responsive materials but also utilized for the immobilization and embedding of biomolecules for applications in wearable devices, fast sensing devices, and other functional materials. The present review delineates the impact of different porphyrinoid conjugates on their physicochemical properties and their specificity as biosensors in a range of applications. The newest porphyrinoid types and their synthesis, modification, and functionalization are presented along with their advantages and performance improvements.

Vesicular Antibodies: Shedding Light on Antibody Therapeutics with Cell Membrane Nanotechnology.

The high stability of antibodies and their ability to precisely bind to antigens and endogenous immune receptors, as well as their susceptibility to protein engineering, enable antibody-based therapeutics to be widely applied in cancer, inflammation, infection, and other disorders. Nevertheless, the application of traditional antibody-based therapeutics has certain limitations, such as high price, limited permeability, and protein engineering complexity. Recent breakthroughs in cell membrane nanotechnology have deepened the understanding of the critical role of membrane protein receptors in disease treatment, enabling vesicular-antibody-based therapeutics. Here, the concept of vesicular antibodies that are obtained by modifying target antibodies onto cell membranes for biomedical applications is proposed. Given that an antibody is basically a protein, as an extension of this concept, vesicles or membrane-coated nanoparticles that use surface antibodies and protein receptors on cell membranes for biomedical applications as vesicular antibodies are defined. Furthermore, several engineering strategies for vesicular antibodies are summarized and how vesicular antibodies can be used in a variety of situations is highlighted. In addition, current challenges and future prospects of vesicular antibodies are also discussed. It is anticipated this perspective will provide new insights on the development of next-generation antibodies for enhanced therapeutics.

Biomimetic manganese-based theranostic nanoplatform for cancer multimodal imaging and twofold immunotherapy.

The limited clinical response and serious side effect have been challenging in cancer immunotherapy resulting from immunosuppressive tumor microenvironment (TME) and inferior drug targeting. Herein, an active targeting TME nanoplatform capable of revising the immunosuppressive TME microenvironment is designed. Briefly, gold nanorods (GNRs) are covered with silica dioxide (SiO2) and then coated manganese dioxide (MnO2) to obtain GNRs@SiO2@MnO2 (GSM). Myeloid-derived suppressor cells (MDSCs) membrane is further camouflaged on the surface of GSM to obtain GNRs@SiO2@MnO2@MDSCs (GSMM). In this system, GSMM inherits active targeting TME capacity of MDSCs. The localized surface plasmon resonance of GNRs is developed in near-infrared II window by MnO2 layer coating, realizing NIR-II window photothermal imaging and photoacoustic imaging of GSMM. Based on the release of Mn2+ in acidic TME, GSMM can be also used for magnetic resonance imaging. In cancer cells, Mn2+ catalyzes H2O2 into ·OH for (chemodynamic therapy) CDT leading to activate cGAS-STING, but also directly acts on STING inducing secretion of type I interferons, pro-inflammatory cytokines and chemokines. Additionally, photothermal therapy and CDT-mediated immunogenic cell death of tumor cells can further enhance anti-tumor immunity via exposure of CRT, HMGB1 and ATP. In summary, our nanoplatform realizes multimodal cancer imaging and dual immunotherapy.

Characteristics of COVID-19 (Delta Variant)/HIV Co-infection: A Cross-sectional Study in Henan Province, China.

Background: Since the end of July 2021, SARS-CoV-2 (Delta variant) invaded Henan Province, China, causing a rapid COVID-19 spread in the province. Among them, the clinical features of COVID-19 (Delta Variant)/HIV co-infection have attracted our attention. Methods: We included 12 COVID-19 patients living with HIV (human immunodeficiency virus) from July 30, 2021 to September 17, 2021 in Henan Province, China. Demographic, clinical, laboratory, and computed tomography (CT) imaging data were dynamically collected from first nucleic acid positive to hospital discharge. Laboratory findings included SARS-CoV-2 viral load, HIV viral load, IgM, IgG, cytokines, lymphocyte subpopulation, ferritin, etc. Statistical analyses were performed using IBM SPSS version 26·0 and GraphPad Prism version 9·0. Results: It was founded that the low Ct value persisted for about 21 days, and the viral shedding time (turn negative time) of the patients was 32·36 ± 2·643 days. Furthermore, chest CT imaging revealed that lesions were obviously and rapidly absorbed. It was surprising that IgM levels were statistically higher in patients taking azvudine or convalescent plasma than in patients not taking these drugs (P < 0·001, P = 0·0002, respectively). IgG levels were significantly higher in patients treated with the combined medication of BRII/196 and BRII/198 than in those not treated with these drugs (P = 0·0029). IgM was significantly higher in those with low HIV viral load than those with high HIV viral load (P < 0·001). In addition, as treatment progressed and patients' condition improved, IL-17a showed a decreasing trend. Conclusions: Based on this study, we found that HIV infection might not exacerbate COVID-19 severity. Supplementary Information: The online version contains supplementary material available at 10.1007/s44231-022-00018-z.

Dendritic Polyglycerol-Conjugated Gold Nanostars for Metabolism Inhibition and Targeted Photothermal Therapy in Breast Cancer Stem Cells.

Breast cancer stem cells (CSCs) are believed to be responsible for tumor initiation, invasion, metastasis, and recurrence, which lead to treatment failure. Thus, developing effective CSC-targeted therapeutic strategies is crucial for enhancing therapeutic efficacy. In this work, GNSs-dPG-3BP, TPP, and HA nanocomposite particles are developed by simultaneously conjugating hexokinase 2 (HK2) inhibitor 3-bromopyruvate (3BP), mitochondrial targeting molecule triphenyl phosphonium (TPP), and CSCs targeting agent hyaluronic acid (HA) onto gold nanostars-dendritic polyglycerol (GNSs-dPG) nanoplatforms for efficient eradication of CSCs. The nanocomposite particles possess good biocompatibility and exhibit superior mitochondrial-bound HK2 binding ability via 3BP to inhibit metabolism, and further induce cellular apoptosis by releasing the cytochrome c. Therefore, it enhanced the therapeutic efficacy of CSCs-specific targeted photothermal therapy (PTT), and achieved a synergistic effect for the eradication of breast CSCs. After administration of the synergistic treatment, the self-renewal of breast CSCs and the stemness gene expression are suppressed, CSC-driven mammosphere formation is diminished, the in vivo tumor growth is effectively inhibited, and CSCs are eradicated. Altogether, GNSs-dPG-3BP, TPP, and HA nanocomposite particles have been developed, which will provide a novel strategy for precise and highly efficient targeted eradication of CSCs.

Gelatinase-sensitive nanoparticles loaded with photosensitizer and STAT3 inhibitor for cancer photothermal therapy and immunotherapy.

Matrix metalloproteinase (MMP) 2 and 9 are the family members of proteases normally up-regulated in tumor to enhance the invasion and metastatic of tumor cells, and are associated with poor outcome of head and neck squamous cell carcinomas (HNSCCs). In the present work, MMPs-degradable gelatin nanoparticles (GNPs) are simultaneously loaded with photosensitizer indocyanine green (ICG) along with signal transducer activator of transcription 3 (STAT3) inhibitor NSC74859 (NSC, N) for efficient photothermal therapy (PTT) and immunotherapy of HNSCCs. In the tumor tissue, Gel-N-ICG nanoparticle was degraded and encapsulated ICG and NSC were effectively released. Under near-infrared (NIR) irradiation, the released ICG nanoparticles enabled effective photothermal destruction of tumors, and the STAT3 inhibitor NSC elicited potent antitumor immunity for enhanced cancer therapy. Based on two HNSCC mouse models, we demonstrated that Gel-N-ICG significantly delayed tumor growth without any appreciable body weight loss. Taken together, the strategy reported here may contribute that the stimuli-responsive proteases triggered nanoplatform could reduce tumor size more effectively in complex tumor microenvironment (TME) through combination of PTT and immunotherapy.

Genetically Programmable Fusion Cellular Vesicles for Cancer Immunotherapy.

Herein, we report that genetically programmable fusion cellular vesicles (Fus-CVs) displaying high-affinity SIRPα variants and PD-1 can activate potent antitumor immunity through both innate and adaptive immune effectors. Dual-blockade of CD47 and PD-L1 with Fus-CVs significantly increases the phagocytosis of cancer cells by macrophages, promotes antigen presentation, and activates antitumor T-cell immunity. Moreover, the bispecific targeting design of Fus-CVs ensures better targeting on tumor cells, but less on other cells, which reduces systemic side effects and enhances therapeutic efficacies. In malignant melanoma and mammary carcinoma models, we demonstrate that Fus-CVs significantly improve overall survival of model animals by inhibiting post-surgery tumor recurrence and metastasis. The Fus-CVs are suitable for protein display by genetic engineering. These advantages, integrated with other unique properties inherited from source cells, make Fus-CVs an attractive platform for multi-targeting immune checkpoint blockade therapy.

Engineered Cell Membrane-Derived Nanoparticles in Immune Modulation.

Immune modulation is one of the most effective approaches in the therapy of complex diseases, including public health emergency. However, most immune therapeutics such as drugs, vaccines, and cellular therapy suffer from the limitations of poor efficacy and adverse side effects. Fortunately, cell membrane-derived nanoparticles (CMDNs) have superior compatibility with other therapeutics and offer new opportunities to push the limits of current treatments in immune modulation. As the interface between cells and outer surroundings, cell membrane contains components which instruct intercellular communication and the plasticity of cytomembrane has significantly potentiated CMDNs to leverage our immune system. Therefore, cell membranes employed in immunomodulatory CMDNs have gradually shifted from natural to engineered. In this review, unique properties of immunomodulatory CMDNs and engineering strategies of emerging CMDNs for immune modulation, with an emphasis on the design logic are summarized. Further, this review points out some pressing problems to be solved during clinical translation and put forward some suggestions on the prospect of immunoregulatory CMDNs. It is anticipated that this review can provide new insights on the design of immunoregulatory CMDNs and expand their potentiation in the precise control of the dysregulated immune system.

Retinoic Acid-Loaded Dendritic Polyglycerol-Conjugated Gold Nanostars for Targeted Photothermal Therapy in Breast Cancer Stem Cells.

The existence of cancer stem cells (CSCs) poses a major obstacle for the success of current cancer therapies, especially the fact that non-CSCs can spontaneously turn into CSCs, which lead to the failure of the treatment and tumor relapse. Therefore, it is very important to develop effective strategies for the eradication of the CSCs. In this work, we have developed a CSCs-specific targeted, retinoic acid (RA)-loaded gold nanostars-dendritic polyglycerol (GNSs-dPG) nanoplatform for the efficient eradication of CSCs. The nanocomposites possess good biocompatibility and exhibit effective CSCs-specific multivalent targeted capability due to hyaluronic acid (HA) decorated on the multiple attachment sites of the bioinert dendritic polyglycerol (dPG). With the help of CSCs differentiation induced by RA, the self-renewal of breast CSCs and tumor growth were suppressed by the high therapeutic efficacy of photothermal therapy (PTT) in a synergistic inhibitory manner. Moreover, the stemness gene expression and CSC-driven tumorsphere formation were significantly diminished. In addition, the in vivo tumor growth and CSCs were also effectively eliminated, which indicated superior anticancer activity, effective CSCs suppression, and prevention of relapse. Taken together, we developed a CSCs-specific targeted, RA-loaded GNSs-dPG nanoplatform for the targeted eradication of CSCs and for preventing the relapse.