Rational strategies for improving the efficiency of design and discovery of nanomedicines.

The rise of rational strategies in nanomedicine development, such as high-throughput methods and computer-aided techniques, has led to a shift in the design and discovery patterns of nanomedicines from a trial-and-error mode to a rational mode. This transition facilitates the enhancement of efficiency in the preclinical discovery pipeline of nanomaterials, particularly in improving the hit rate of nanomaterials and the optimization efficiency of promising candidates. Herein, we describe a directed evolution mode of nanomedicines driven by data to accelerate the discovery of nanomaterials with high delivery efficiency.

Confined copper depletion via a hydrogel platform for reversing dabrafenib/cetuximab resistance in BRAF-mutant colorectal cancer.

BRAF-mutant colorectal cancer (CRC) is resistant to most first-line therapeutics, including the BRAF inhibitor dabrafenib and epidermal growth factor receptor (EGFR) inhibitor cetuximab. Although copper depletion shows promise in reversing dabrafenib/cetuximab resistance in BRAF-mutant CRC, its application is limited by the potential for excessive copper depletion in non-tumor objects. In this study, we have developed a hydrogel platform for confined copper depletion in BRAF-mutant CRC cells, which effectively reverses dabrafenib/cetuximab resistance and enhancing therapeutic efficiency.

Versatile biomimetic nanomedicine for treating cancer and inflammation disease.

Nanosized drug delivery systems (NDDSs) have emerged as a powerful tool to optimize drug delivery in complex diseases, including cancer and inflammation. However, the therapeutic effect of NDDSs is still far from satisfactory due to their poor circulation time, low delivery efficiency, and innate toxicity. Fortunately, biomimetic approaches offer new opportunities to develop nanomedicine, which is derived from a variety of native biomolecules including cells, exosomes, bacteria, and so on.

STING agonist-boosted mRNA immunization via intelligent design of nanovaccines for enhancing cancer immunotherapy.

Messenger RNA (mRNA) vaccine is revolutionizing the methodology of immunization in cancer. However, mRNA immunization is drastically limited by multistage biological barriers including poor lymphatic transport, rapid clearance, catalytic hydrolysis, insufficient cellular entry and endosome entrapment. Herein, we design a mRNA nanovaccine based on intelligent design to overcome these obstacles.

Acid-switchable nanoparticles induce self-adaptive aggregation for enhancing antitumor immunity of natural killer cells.

Deficiency of natural killer (NK) cells shows a significant impact on tumor progression and failure of immunotherapy. It is highly desirable to boost NK cell immunity by upregulating active receptors and relieving the immunosuppressive tumor microenvironment. Unfortunately, mobilization of NK cells is hampered by poor accumulation and short retention of drugs in tumors, thus declining antitumor efficiency.

Smart drug delivery systems to overcome drug resistance in cancer immunotherapy.

Cancer immunotherapy, a therapeutic approach that inhibits tumors by activating or strengthening anti-tumor immunity, is currently an important clinical strategy for cancer treatment; however, tumors can develop drug resistance to immune surveillance, resulting in poor response rates and low therapeutic efficacy. In addition, changes in genes and signaling pathways in tumor cells prevent susceptibility to immunotherapeutic agents. Furthermore, tumors create an immunosuppressive microenvironment immunosuppressive cells and secrete molecules that hinder immune cell and immune modulator infiltration or induce immune cell malfunction.

Recent advances in developing active targeting and multi-functional drug delivery systems via bioorthogonal chemistry.

Bioorthogonal chemistry reactions occur in physiological conditions without interfering with normal physiological processes. Through metabolic engineering, bioorthogonal groups can be tagged onto cell membranes, which selectively attach to cargos with paired groups via bioorthogonal reactions. Due to its simplicity, high efficiency, and specificity, bioorthogonal chemistry has demonstrated great application potential in drug delivery.

Blocking Cholesterol Metabolism with Tumor-Penetrable Nanovesicles to Improve Photodynamic Cancer Immunotherapy.

Photodynamic therapy (PDT)-mediated cancer immunotherapy is attenuated due to the dysfunction of T cells in immunosuppressive tumor microenvironment (TME). Cholesterol metabolism plays a vital role in T cell signaling and effector. While the metabolic fitness of tumor infiltrating CD8 T cells is impaired by nutrition restriction in TME and accumulated metabolites by tumor cells.

Walking Dead Tumor Cells for Targeted Drug Delivery Against Lung Metastasis of Triple-Negative Breast Cancer.

Lung metastasis is challenging in patients with triple-negative breast cancer (TNBC). Surgery is always not available due to the dissemination of metastatic foci and most drugs are powerless because of poor retention at metastatic sites. TNBC cells generate an inflamed microenvironment and overexpress adhesive molecules to promote invasion and colonization.

Dual-responsive nanoparticles loading bevacizumab and gefitinib for molecular targeted therapy against non-small cell lung cancer.

The combination of vascular endothelial growth factor (VEGF) inhibitors and tyrosine kinase inhibitors (TKIs) is newly available for molecular targeted therapy against non-small cell lung cancer (NSCLC) in clinic. However, the therapeutic benefits remain unsatisfying due to the poor drug delivery to targets of interest. In this study, we developed bevacizumab-coated gefitinib-loaded nanoparticles (BCGN) with dual-responsive drug release for inhibiting tumor angiogenesis and phosphorylation of epidermal growth factor receptor (EGFR).

Light-controllable charge-reversal nanoparticles with polyinosinic-polycytidylic acid for enhancing immunotherapy of triple negative breast cancer.

Nucleic acid drugs are highly applicable for cancer immunotherapy with promising therapeutic effects, while targeting delivery of these drugs to disease lesions remains challenging. Cationic polymeric nanoparticles have paved the way for efficient delivery of nucleic acid drugs, and achieved stimuli-responsive disassembly in tumor microenvironment (TME). However, TME is highly heterogeneous between individuals, and most nanocarriers lack active-control over the release of loaded nucleic acid drugs, which will definitely reduce the therapeutic efficacy.

Engineering Nanoscale Artificial Antigen-Presenting Cells by Metabolic Dendritic Cell Labeling to Potentiate Cancer Immunotherapy.

Nanoscale artificial antigen-presenting cells (aAPCs) are promising to activate T cells directly for cancer immunotherapy, while feasible and flexible strategy to develop nanoscale aAPCs remains highly desirable. Metabolic glycoengineering is used to decorate chemical tags on cells which enables bioorthogonal chemical conjugation of functional molecules. Herein, we develop a nanoscale aAPC by metabolic dendritic cell (DC) labeling to mobilize T-cell based antitumor immunity.

Smart Nanosized Drug Delivery Systems Inducing Immunogenic Cell Death for Combination with Cancer Immunotherapy.

Cancer immunotherapy, which suppresses tumor relapse and metastasis by boosting host immunity and inducing long-term immune memory effects, is emerging as a vital approach to improve the prognosis of patients. Although remarkable efficacy has been observed in some patients, challenges including low response rate, drug resistance, and immune-related adverse effects still limit the clinical application of cancer immunotherapy in broad types of tumors. Immunotherapeutic agents are used to enhance tumor immunogenicity and reverse the effects of the immunosuppressive tumor microenvironment (ITM), but the benefits of monotherapy are mild and transient due to off-target distribution of drugs.

Engineering autologous tumor cell vaccine to locally mobilize antitumor immunity in tumor surgical bed.

Autologous tumor cell-based vaccines (ATVs) are emerging as a transformable approach for personalized immunotherapy, but their therapeutic efficacy remains unsatisfying in patients with cancer. Here, we design a photodynamic therapy (PDT)-motivated ATV (P-ATV) in Fmoc-KCRGDK-phenylboronic acid (FK-PBA) hydrogel, which mobilizes local immune activation to inhibit relapse of postoperative tumors. The FK-PBA targeting overexpressed sialic acid on tumor cells can enable on-demand gelation in residue tumor areas and maintain continuous vaccination in surgical bed.

Engineering Polymeric Prodrug Nanoplatform for Vaccination Immunotherapy of Cancer.

Neoantigen-based cancer vaccines are promising for boosting cytotoxic T lymphocyte (CTL) responses. However, the therapeutic effect of cancer vaccines is severely blunted by functional suppression of the dendritic cells (DCs). Herein, we demonstrated an acid-responsive polymeric nanovaccine for activating the stimulator of interferon genes (STING) pathway and improving cancer immunotherapy.

Engineering Stimuli-Activatable Boolean Logic Prodrug Nanoparticles for Combination Cancer Immunotherapy.

Prodrug nanoparticles that codeliver the immune modulators to the tumor site are highly recommendable for cancer immunotherapy yet remain challenging. However, effective stimuli-responsive strategies that exploit the endogenous hallmarks of the tumor have paved the way for cancer immunotherapy. For the first time, the development of the Boolean logic prodrug nanoparticles (BLPNs) for tumor-targeted codelivery of immune modulators (e.

Engineering nanoparticles to locally activate T cells in the tumor microenvironment.

Immunological tolerance of tumors is characterized by insufficient infiltration of cytotoxic T lymphocytes (CTLs) and immunosuppressive microenvironment of tumor. Tumor resistance to immune checkpoint inhibitors due to immunological tolerance is an ongoing challenge for current immune checkpoint blockade (ICB) therapy. Here, we report the development of tumor microenvironment-activatable anti-PDL1 antibody (αPDL1) nanoparticles for combination immunotherapy designed to overcome immunological tolerance of tumors.

Non-viral gene delivery for cancer immunotherapy.

Recent decades have witnessed the revolutionary development of cancer immunotherapies, which boost cancer-specific immune responses for long-term tumor regression. However, immunotherapy still has limitations, including off-target side effects, long processing times and limited patient responses. These disadvantages of current immunotherapy are being addressed by improving our understanding of the immune system, as well as by establishing combinational approaches.

Improving Cancer Vaccine Efficiency by Nanomedicine.

Cancer vaccines, which have been widely investigated in the past few decades, are one of the most attractive strategies for cancer immunotherapy. Through the precise delivery of antigens and adjuvants to lymphoid organs or lymphocytes via nanotechnology, innate and adaptive immunity can be boosted to prevent the growth and relapse of malignant tumors. Indeed, nanomedicine offers great opportunities to improve the efficiency of vaccines.

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.

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.

A cancer vaccine-mediated postoperative immunotherapy for recurrent and metastatic tumors.

Vaccines to induce effective and sustained antitumor immunity have great potential for postoperative cancer therapy. However, a robust cancer vaccine simultaneously eliciting tumor-specific immunity and abolishing immune resistance continues to be a challenge. Here we present a personalized cancer vaccine (PVAX) for postsurgical immunotherapy.

Acidity-Triggered Ligand-Presenting Nanoparticles To Overcome Sequential Drug Delivery Barriers to Tumors.

The success of cancer chemotherapy is impeded by poor drug delivery efficiency due to the existence of a series of pathophysiological barriers in the tumor. In this study, we reported a tumor acidity-triggered ligand-presenting (ATLP) nanoparticle for cancer therapy. The ATLP nanoparticles were composed of an acid-responsive diblock copolymer as a sheddable matrix and an iRGD-modified polymeric prodrug of doxorubicin (iPDOX) as an amphiphilic core.

Core-shell hierarchical mesostructured silica nanoparticles for gene/chemo-synergetic stepwise therapy of multidrug-resistant cancer.

The design and synthesis of hierarchically nanoporous structures for the co-encapsulation and sequential releases of different cargos are still great challenges in biomedical applications. In this work, we report on the elaborate design and controlled synthesis of a unique core-shell hierarchical mesoporous silica/organosilica nanosystem, in which there are large and small mesopores separately present in the shell and core, facilitating the independent encapsulations of large (siRNA) and small (doxorubicin) molecules, respectively. Importantly, the framework of the organosilica shell is molecularly hybridized with disulfide bonds, which enables the unique responsiveness to the reductive tumor microenvironment for the controlled releasing of loaded gene molecules, followed by the subsequent doxorubicin release.

Phospholipid-mimic oxaliplatin prodrug liposome for treatment of the metastatic triple negative breast cancer.

A phospholipid-mimic oxaliplatin prodrug (Oxalipid) was synthesized, which could self-assemble into a liposomal nanostructure with a drug loading ratio as high as 27 wt%. Compared to free oxaliplatin, the resulting Oxalipid liposome displayed elongated blood circulation, increased tumor accumulation and improved anticancer efficacy against the metastatic triple negative breast cancer (TNBC).