Biomimetic biomineralization nanoplatform-mediated differentiation therapy and phototherapy for cancer stem cell inhibition and antitumor immunity activation.

Growing evidence suggests that the presence of cancer stem cells (CSCs) is a major challenge in current tumor treatments, especially the transition from non-CSCs to differentiation of CSCs for evading conventional therapies and driving metastasis. Here we propose a therapeutic strategy of synergistic differentiation therapy and phototherapy to induce differentiation of CSCs into mature tumor cells by differentiation inducers and synergistic elimination of them and normal cancer cells through phototherapy. In this work, we synthesized a biomimetic nanoplatform loaded with IR-780 and all-trans retinoic acid (ATRA) via biomineralization. This method can integrate aluminum ions into small-sized protein carriers to form nanoclusters, which undergo responsive degradation under acidic conditions and facilitate deep tumor penetration. With the help of CSC differentiation induced by ATRA, IR-780 inhibited the self-renewal of CSCs and cancer progression by generating hyperthermia and reactive oxygen species in a synergistic manner. Furthermore, ATRA can boost immunogenic cell death induced by phototherapy, thereby strongly causing a systemic anti-tumor immune response and efficiently eliminating CSCs and tumor cells. Taken together, this dual strategy represents a new paradigm of targeted eradication of CSCs and tumors by inducing CSC differentiation, improving photothermal therapy/photodynamic therapy and enhancing antitumor immunity.

Oxygen-boosted biomimetic nanoplatform for synergetic phototherapy/ferroptosis activation and reversal of immune-suppressed tumor microenvironment.

Photodynamic therapy (PDT) induces apoptosis of cancer cells by generating cytotoxic reactive oxygen species, the therapeutic effect of which, however, is impeded by intrinsic/inducible apoptosis-resistant mechanisms in cancer cells and hypoxia of tumor microenvironment (TME); also, PDT-induced anti-tumor immunity activation is insufficient. To deal with these obstacles, a novel biomimetic nanoplatform is fabricated for the precise delivery of photosensitizer chlorin e6 (Ce6), hemin and PEP20 (CD47 inhibitory peptide), integrating oxygen-boosted PDT, ferroptosis activation and CD47-SIRPα blockade. Hemin's catalase-mimetic activity alleviates TME hypoxia and enhances PDT. The nanoplatform activates ferroptosis via both classical (down-regulating glutathione peroxidase 4 pathway) and non-classical (inducing Fe2+ overload) modes. Besides the role of hemin in consuming glutathione and up-regulating heme oxygenase-1 expression, interestingly, we observe that Ce6 enhance ferroptosis activation via both classical and non-classical modes. The anti-cancer immunity is reinforced by combining PEP20-mediated CD47-SIRPα blockade and PDT-mediated T cell activation, efficiently suppressing primary tumor growth and metastasis. PEP20 has been revealed for the first time to sensitize ferroptosis by down-regulating system Xc-. This work sheds new light on the mechanisms of PDT-ferroptosis activation interplay and bridges immunotherapy and ferroptosis activation, laying the theoretical foundation for novel combinational modes of cancer treatment.

A molybdenum oxide-based degradable nanosheet for combined chemo-photothermal therapy to improve tumor immunosuppression and suppress distant tumors and lung metastases.

Molybdenum oxide (MoOx) nanosheets have drawn increasing attention for minimally invasive cancer treatments but still face great challenges, including complex modifications and the lack of efficient accumulation in tumor. In this work, a novel multifunctional degradable FA-BSA-PEG/MoOx nanosheet was fabricated (LA-PEG and FA-BSA dual modified MoOx): the synergistic effect of PEG and BSA endows the nanosheet with excellent stability and compatibility; the FA, a targeting ligand, facilitates the accumulation of nanosheets in the tumor. In addition, DTX, a model drug for breast cancer treatment, was loaded (76.49%, 1.5 times the carrier weight) in the nanosheets for in vitro and in vivo antitumor evaluation. The results revealed that the FA-BSA-PEG/MoOx@DTX nanosheets combined photothermal and chemotherapy could not only inhibit the primary tumor growth but also suppress the distant tumor growth (inhibition rate: 51.7%) and lung metastasis (inhibition rate: 93.6%), which is far more effective compared to the commercial Taxotere®. Exploration of the molecular mechanism showed that in vivo immune response induced an increase in positive immune responders, suppressed negative immune suppressors, and established an inflammatory tumor immune environment, which co-contributes towards effective suppression of tumor and lung metastasis. Our experiments demonstrated that this novel multifunctional nanosheet is a promising platform for combined chemo-photothermal therapy.

NIR-triggerable ROS-responsive cluster-bomb-like nanoplatform for enhanced tumor penetration, phototherapy efficiency and antitumor immunity.

The restricted tumor penetration has been regarded as the Achilles' Heels of most nanomedicines, largely limiting their efficacy. To address this challenge, a cluster-bomb-like nanoplatform named CPIM is prepared, which for the first time combines size-transforming and transcytosis strategies, thus enhancing both passive and active transport. For passive diffusion, the "cluster-bomb" CPIM (135 nm) releases drug-loaded "bomblets" (IR780/1-methyl-tryptophan (1 MT) loaded PAMAM, <10 nm) in response to the high reactive-oxygen-species (ROS) concentration in tumor microenvironment (TME), which promotes intratumoral diffusion. Besides, IR780 generates ROS upon NIR irradiation and intensifies this responsiveness; therefore, there exists a NIR-triggered self-destructive behavior, rendering CPIM spatiotemporal controllability. For active transport, the nanoplatform is proven to be delivered via transcytosis with/without NIR irradiation. Regarding the anti-cancer performance, CPIM strengthens the photodynamic therapy (PDT)/photothermal therapy (PTT) activity of IR780 and IDO pathway inhibition effect of 1 MT, thus exhibiting a strongest inhibitory effect on primary tumor. CPIM also optimally induces immunogenic cell death, reverses the "cold" TME to a "hot" one and evokes systemic immune response, thus exerting an abscopal and anti-metastasis effects. In conclusion, this work provides a facile, simple yet effective strategy to enhance the tumor penetration, tumor-killing effect and antitumor immunity of nanomedicines.

The role of glycyrrhetinic acid modification on preparation and evaluation of quercetin-loaded chitosan-based self-aggregates.

Quercetin (QC), a type of plant-based chemical, has been reported to own anticancer activity in vivo. However, the poor water solubility limits its pharmaceutical application. In this study, two kinds of QC-loaded self-aggregates based on O-carboxymethyl chitosan-cholic acid conjugates (CMCA) were developed to improve the drug bioavailability in which glycyrrhetinic acid (GA) modification was utilized in the nanocarrier fabrication (QC-GA-CMCA) or not (QC-CMCA). These self-aggregates were prepared by a modified ultrasound-dialysis method and the role of GA modification on the evaluation of QC-loaded self-aggregates was investigated. Transmission Electron Microscopy (TEM) images revealed the formation of spherical particles of both self-aggregates. Dynamic Light Scattering (DLS) analysis and UV-VIS spectroscopy showed that the QC-GA-CMCA had smaller size, narrower size distribution, higher drug loading and entrapment efficiency than corresponding QC-CMCA aggregates. QC-GA-CMCA showed more obvious sensitivity to acidic pH condition based on the zeta potential measurements at various pHs, and fastest drug release was observed at pH 5.7 for QC-CMCA while at pH 6.5 for QC-GA-CMCA. In addition, QC-GA-CMCA demonstrated enhanced cell cytotoxicity and higher cell apoptosis rate in vitro, and also higher AUC value and a prolonged residence time of drug in vivo.