Cancer immunotherapy, as a paradigm shift in cancer treatment, has recently received tremendous attention. The active cancer vaccination, immune checkpoint blockage (ICB) and chimeric antigen ...receptor (CAR) for T‐cell‐based adoptive cell transfer are among these developments that have achieved a significant increase in patient survival in clinical trials. Despite these advancements, emerging research at the interdisciplinary interface of cancer biology, immunology, bioengineering, and materials science is important to further enhance the therapeutic benefits and reduce side effects. Here, an overview of the latest studies on engineering biomaterials for the enhancement of anticancer immunity is given, including the perspectives of delivery of immunomodulatory therapeutics, engineering immune cells, and constructing immune‐modulating scaffolds. The opportunities and challenges in this field are also discussed.
Cancer immunotherapy has recently received tremendous attention and has created a paradigm shift in the treatment of cancer. An overview of the latest studies on tailoring biomaterials for enhancement of anticancer immunity is presented, including delivery of therapeutics to antigen‐presenting cells, delivery of therapeutics to the tumor microenvironment, engineering of immune cells, and constructing immune scaffolds.
Immunosuppressive cells residing in the tumor microenvironment, especially tumor associated macrophages (TAMs), hinder the infiltration and activation of T cells, limiting the anti-cancer outcomes of ...immune checkpoint blockade. Here, we report a biocompatible alginate-based hydrogel loaded with Pexidartinib (PLX)-encapsulated nanoparticles that gradually release PLX at the tumor site to block colony-stimulating factor 1 receptors (CSF1R) for depleting TAMs. The controlled TAM depletion creates a favorable milieu for facilitating local and systemic delivery of anti-programmed cell death protein 1 (aPD-1) antibody-conjugated platelets to inhibit post-surgery tumor recurrence. The tumor immunosuppressive microenvironment is also reprogrammed by TAM elimination, further promoting the infiltration of T cells into tumor tissues. Moreover, the inflammatory environment after surgery could trigger the activation of platelets to facilitate the release of aPD-1 accompanied with platelet-derived microparticles binding to PD-1 receptors for re-activating T cells. All these results collectively indicate that the immunotherapeutic efficacy against tumor recurrence of both local and systemic administration of aPD-1 antibody-conjugated platelets could be strengthened by local depletion of TAMs through the hydrogel reservoir.
Proteolysis Targeting Chimeras (PROTACs), an emerging therapeutic entity designed to degrade target proteins by hijacking the ubiquitinproteasome system, have the potential to revolutionize the ...healthcare industry. The broad applicability of this protein degradation strategy has been verified with a few E3 ligases and a variety of distinct targets through the construction of modular chimeric structures. Despite recent efforts to promote the use of PROTACs for clinical applications, most PROTACs do not make it beyond the preclinical stage of drug development. There are several reasons that prevent PROTACs from reaching the market, and the inadequate delivery to the target site is one of the most challenging hurdles. With the increasing need for accelerating the translational process, combining the concepts of PROTACs and delivery systems has been explored to enhance the
in vivo
performance of PROTACs. These improved delivery strategies can eliminate unfavorable physicochemical properties of PROTACs, improve their targetability, and decrease their off-target side effects. The integration of powerful PROTACs and versatile delivery systems will inaugurate a burgeoning orientation for the field of targeted protein degradation. In this review, we will survey the latest progress in improving the
in vivo
degradation efficacy of PROTACs through delivery strategies, outline design principles for PROTAC-based delivery systems, discuss the current challenges with PROTACs, and outlook future opportunities in this field.
This tutorial review discusses the convergence of drug delivery systems and PROTACs, surveys the burgeoning PROTAC delivery strategies, summarizes their design principles, clarifies their challenges, and outlooks future translational opportunities.
A core–shell nanovehicle coated with a platelet membrane (PM) is developed for targeted and site‐specific delivery of an extracellularly active drug and an intracellular functional small‐molecular ...drug, leading to enhanced antitumor efficacy. This PM‐coated nanovehicle can also effectively eliminate the circulating tumor cells in vivo and inhibit development of tumor metastasis.
CRISPR–Cas9 represents a promising platform for genome editing, yet means for its safe and efficient delivery remain to be fully realized. A novel vehicle that simultaneously delivers the Cas9 ...protein and single guide RNA (sgRNA) is based on DNA nanoclews, yarn‐like DNA nanoparticles that are synthesized by rolling circle amplification. The biologically inspired vehicles were efficiently loaded with Cas9/sgRNA complexes and delivered the complexes to the nuclei of human cells, thus enabling targeted gene disruption while maintaining cell viability. Editing was most efficient when the DNA nanoclew sequence and the sgRNA guide sequence were partially complementary, offering a design rule for enhancing delivery. Overall, this strategy provides a versatile method that could be adapted for delivering other DNA‐binding proteins or functional nucleic acids.
All rolled into one: A biologically inspired delivery vehicle for CRISPR–Cas9 is based on yarn‐like DNA nanoparticles that are synthesized by rolling circle amplification. The DNA nanoclews were efficiently loaded with Cas9 protein/single guide RNA complexes and delivered them into human cells, enabling targeted gene disruption.
Immunotherapy strategies that use cell‐based delivery systems have sparked much interest in the treatment of malignancies, owing to their high biocompatibility, excellent tumor targeting capability, ...and unique biofunctionalities in the tumor growth process. A variety of design principles for cell‐based immunotherapy, including cell surface decoration, cell membrane coating, cell encapsulation, genetically engineered cell, and cell‐derived exosomes, give cancer immunotherapy great potential to improve therapeutic efficacy and reduce adverse effects. However, the treatment efficacy of cell‐based delivery methods for immunotherapy is still limited, and practical uses are hampered due to complex physiological and immunological obstacles, such as physical barriers to immune infiltration, immunosuppressive tumor microenvironment, upregulation of immunosuppressive pathways, and metabolic restriction. In this review, we present an overview of the design principles of cell‐based delivery systems in cancer immunotherapy to maximize the therapeutic impact, along with anatomical, metabolic, and immunological impediments in using cell‐based immunotherapy to treat cancer. Following that, a summary of novel delivery strategies that have been created to overcome these obstacles to cell‐based immunotherapeutic delivery systems is provided. Also, the obstacles and prospects of next‐step development of cell‐based delivery systems for cancer immunotherapy are concluded in the end.
This review covers the design of cell‐based delivery systems for cancer immunotherapy, as well as the significant challenges limiting the efficacy of cell‐based immunotherapy and summarizes recent advances in overcoming those barriers to improve cancer treatment outcomes.
Ischemic stroke caused by a thrombus clog and ischemia is one of the most lethal and disabling cerebrovascular diseases. A sequentially targeted delivery system is highly desired to deliver ...thrombolytics and neuroprotectant to the site of the thrombus and ischemic penumbra, respectively, to pursue a maximized combinational effect. Inspired by the vital roles that platelets play in thrombus formation, herein, we develop a bioengineered “nanoplatelet” (tP-NP-rtPA/ZL006e) for sequentially site-specific delivery of recombinant tissue plasminogen activator (rtPA) and neuroprotectant (ZL006e) for ischemic stroke treatment. The tP-NP-rtPA/ZL006e consists of a ZL006e-loaded dextran derivative polymeric nanoparticle core and platelet membrane shell conjugated with thrombin-cleavable Tat-peptide-coupled rtPA. Mediated by the cloak of the platelet membrane, tP-NP-rtPA/ZL006e targets the thrombus site and rtPA is triggered to release by the upregulated thrombin. Subsequently, the in situ exposed Tat peptide enhanced penetration of the “nanoplatelet” across the blood–brain barrier into ischemic brain for ZL006e site-specific delivery. From the in vitro and in vivo evaluation, tP-NP-rtPA/ZL006e is demonstrated to significantly enhance the anti-ischemic stroke efficacy in the rat model with middle cerebral artery occlusion, showing a 63 and 72% decrease in ischemic area and reactive oxygen species level compared to that with free drug combination, respectively.
The capping agents for liquid metal (LM) nanodroplets in aqueous solutions are restricted to thiol-containing and positively-charged molecules or macromolecules. However, both thiolate-metal complex ...and electrostatic interaction are liable to detachment upon strong mechanical forces such as sonication, leading to limited stability and applications. To address this, we utilized ultrasmall water soluble melanin nanoparticles (MNPs) as the capping agent, which exhibited strong metal binding capability with the oxide layer of gallium based LMs and resulted in enhanced stability. Interestingly, shape-controlled synthesis of LM nanodroplets can be achieved by the incorporation of MNPs. Various EGaIn nanostructures including nanorice, nanosphere and nanorod were obtained by simply tuning the feed ratio, sonication time, and suspension temperature. Among these shapes, EGaIn nanorice has the best photothermal conversion efficiency, which could be leveraged for photothermal therapy.
A light‐activated hypoxia‐responsive conjugated polymer‐based nanocarrier is developed for efficiently producing singlet oxygen (1O2) and inducing hypoxia to promote release of its cargoes in tumor ...cells, leading to enhanced antitumor efficacy. This dual‐responsive nanocarrier provides an innovative design guideline for enhancing traditional photodynamic therapeutic efficacy integrated with a controlled drug‐release modality.
Cancer cells resist to the host immune antitumor response via multiple suppressive mechanisms, including the overexpression of PD‐L1 that exhausts antigen‐specific CD8+ T cells through PD‐1 ...receptors. Checkpoint blockade antibodies against PD‐1 or PD‐L1 have shown unprecedented clinical responses. However, limited host response rate underlines the need to develop alternative engineering approaches. Here, engineered cellular nanovesicles (NVs) presenting PD‐1 receptors on their membranes, which enhance antitumor responses by disrupting the PD‐1/PD‐L1 immune inhibitory axis, are reported. PD‐1 NVs exhibit a long circulation and can bind to the PD‐L1 on melanoma cancer cells. Furthermore, 1‐methyl‐tryptophan, an inhibitor of indoleamine 2,3‐dioxygenase can be loaded into the PD‐1 NVs to synergistically disrupt another immune tolerance pathway in the tumor microenvironment. Additionally, PD‐1 NVs remarkably increase the density of CD8+ tumor infiltrating lymphocytes in the tumor margin, which directly drive tumor regression.
Cellular nanovesicles (NVs) presenting PD‐1 receptors on their membrane are genetically engineered for disturbing the PD1/PD‐L1 immune inhibitory axis. Additionally, 1‐methyl‐tryptophan (1‐MT), an inhibitor of indoleamine 2,3‐dioxygenase (IDO) can be loaded into the PD‐1 NVs to synergistically promote antitumor efficacy. This formulation provides a promising strategy that leverages functions of immune checkpoint blockade and encapsulated therapeutics for enhancing cancer immunotherapy.
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