Multistage Self-Assembled Nanomaterials for Cancer Immunotherapy.

Advances in nanotechnology have brought innovations to cancer therapy. Nanoparticle-based anticancer drugs have achieved great success from bench to bedside. However, insufficient therapy efficacy due to various physiological barriers in the body remains a key challenge. To overcome these biological barriers and improve the therapeutic efficacy of cancers, multistage self-assembled nanomaterials with advantages of stimuli-responsiveness, programmable delivery, and immune modulations provide great opportunities. In this review, we describe the typical biological barriers for nanomedicines, discuss the recent achievements of multistage self-assembled nanomaterials for stimuli-responsive drug delivery, highlighting the programmable delivery nanomaterials, in situ transformable self-assembled nanomaterials, and immune-reprogramming nanomaterials. Ultimately, we perspective the future opportunities and challenges of multistage self-assembled nanomaterials for cancer immunotherapy.

Metal Ion-Based Supramolecular Self-Assembly for Cancer Theranostics.

Metal-ion-based self-assembly supramolecular theranostics exhibit excellent performance in biomedical applications owing to their potential superiorities for simultaneous precise diagnosis, targeted drug delivery, and monitoring the response to therapy in real-time. Specially, the rational designed systems could achieve specific in vivo self-assembly through complexation or ionic interaction to improve tissue-specific accumulation, penetration, and cell internalization, thereby reducing toxicities of drugs in diagnostics and therapy. Furthermore, such imaging traceable nanosystems could provide real-timely information of drug accumulation and therapeutic effects in a non-invasive and safe manner. Herein, the article highlights the recent prominent applications based on the metal ions self-assembly in cancer treatment. This strategy may open up new research directions to develop novel drug delivery systems for cancer theranostics.

In vivo self-assembled drug nanocrystals for metastatic breast cancer all-stage targeted therapy.

Chemotherapy is still the mainstay treatment for metastatic triple-negative breast cancers (TNBC) currently in clinical practice. The unmet needs of chemotherapy for metastatic TNBC are mainly from the insufficient drug delivery and unavailable targeting strategy that thwart the whole progression of metastatic TNBC. The in vivo ligands-mediated active targeting efficiency is usually affected by protein corona. While, the protein corona-bridged natural targeting, in turn, provides a new way for specific drug delivery. Herein, we develop a novel metastatic progression-oriented in vivo self-assembled Cabazitaxel nanocrystals (CNC) delivery system (PC/CNC) through the CNC automatically absorbing functional plasma proteins (transferrin, apolipoprotein A-IV and apolipoprotein E) in vivo, aiming to achieve the simultaneously targeted delivery to primary tumors, circulating tumor cells and metastatic lesions. With the unique advantages of superhigh drug-loading and protein corona empowered active targeting properties to tumor cells, HUVECs, active-platelets and blood-brain barrier/blood-tumor barrier, the PC/CNC exhibits a significantly improved therapeutic effect in metastatic TNBC therapy compared with free drug and CNC-loaded liposomes.

Tumor Receptor-Mediated In Vivo Modulation of the Morphology, Phototherapeutic Properties, and Pharmacokinetics of Smart Nanomaterials.

To be clinically efficacious, nanotherapeutic drugs need to reach disease tissues reliably and cause limited side effects to normal organs and tissues. Here, we report a proof-of-concept study on the development of a smart peptidic nanophototherapeutic agent in line with clinical requirements, which can transform its morphology from nanoparticles to nanofibrils at the tumor sites. This in vivo receptor-mediated transformation process resulted in the formation and prolonged tumor-retention of highly ordered (J-aggregate type of photosensitizer) photosensitive peptide nanofibrillar network with greatly enhanced photothermal and photodynamic properties. This strategy of "multiple daily low-intensity laser radiation after each intravenous injection of significantly low-dose of nanomaterials" demonstrated effective elimination of 4T1 orthotopic syngeneic breast cancer in mice. The technology for nanomaterial modulation based on living cell surface receptors, in this case tumor-associated α3ß1 integrin, has great potential for clinical translation and is expected to improve the therapeutic efficacy against many cancers.

In Vivo Assembly of Nanoparticles Achieved through Synergy of Structure-Based Protein Engineering and Synthetic DNA Generates Enhanced Adaptive Immunity.

Nanotechnologies are considered to be of growing importance to the vaccine field. Through decoration of immunogens on multivalent nanoparticles, designed nanovaccines can elicit improved humoral immunity. However, significant practical and monetary challenges in large-scale production of nanovaccines have impeded their widespread clinical translation. Here, an alternative approach is illustrated integrating computational protein modeling and adaptive electroporation-mediated synthetic DNA delivery, thus enabling direct in vivo production of nanovaccines. DNA-launched nanoparticles are demonstrated displaying an HIV immunogen spontaneously self-assembled in vivo. DNA-launched nanovaccines induce stronger humoral responses than their monomeric counterparts in both mice and guinea pigs, and uniquely elicit CD8+ effector T-cell immunity as compared to recombinant protein nanovaccines. Improvements in vaccine responses recapitulate when DNA-launched nanovaccines with alternative scaffolds and decorated antigen are designed and evaluated. Finally, evaluation of functional immune responses induced by DLnanovaccines demonstrates that, in comparison to control mice or mice immunized with DNA-encoded hemagglutinin monomer, mice immunized with a DNA-launched hemagglutinin nanoparticle vaccine fully survive a lethal influenza challenge, and have substantially lower viral load, weight loss, and influenza-induced lung pathology. Additional study of these next-generation in vivo-produced nanovaccines may offer advantages for immunization against multiple disease targets.

Acid-Induced In Vivo Assembly of Gold Nanoparticles for Enhanced Photoacoustic Imaging-Guided Photothermal Therapy of Tumors.

The complexity of biological systems poses a great challenge in the development of nanotheranostic agents with enhanced therapeutic efficacies. To systematically overcome a series of barriers during in vivo administration and achieve optimal antitumor activity, nanotheranostic agents that can self-adaptively change their properties in response to certain tumor-associated signals are highly preferable. Herein, gold nanoparticles with a mixed-charge zwitterionic surface (Au-MUA-TMA) is fabricated, which can undergo pH-triggered self-assembly for promoting tumor targeting and improving photoacoustic imaging (PAI)-guided photothermal tumor ablation. In blood and normal tissues, relatively small-sized Au-MUA-TMA can circulate stably, and upon arriving at the tumor sites, they quickly assemble into larger aggregates in an acidic tumor environment to ensure higher tumor accumulation and retention. Furthermore, the absorption band of Au-MUA-TMA can be remarkably shifted to the near-infrared (NIR) region, which effectively activates the photoacoustic (PA) signals of tumors and enhances photothermal therapy (PTT) with minimal side effects. This in vivo self-assembly strategy enables the nanotheranostic agents to better fulfill multiple requirements for in vivo application, thereby attaining advanced performances in cancer diagnosis and treatment.