Tailoring Biomaterials for Cancer Immunotherapy: Emerging Trends and Future Outlook

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.     

Nanoparticle‐Based Nanomedicines to Promote Cancer Immunotherapy: Recent Advances and Future Directions

Cancer immunotherapy is a promising cancer terminator by directing the patient's own immune system in the fight against this challenging disorder. Despite the monumental therapeutic potential of several immunotherapy strategies in clinical applications, the efficacious responses of a wide range of immunotherapeutic agents are limited in virtue of their inadequate accumulation in the tumor tissue and fatal side effects. In the last decades, increasing evidences disclose that nanotechnology acts as an appealing solution to address these technical barriers via conferring rational physicochemical properties to nanomaterials. In this Review, an imperative emphasis will be drawn from the current understanding of the effect of a nanosystem's structure characteristics (e.g., size, shape, surface charge, elasticity) and its chemical modification on its transport and biodistribution behavior. Subsequently, rapid‐moving advances of nanoparticle‐based cancer immunotherapies are summarized from traditional vaccine strategies to recent novel approaches, including delivery of immunotherapeutics (such as whole cancer cell vaccines, immune checkpoint blockade, and immunogenic cell death) and engineered immune cells, to regulate tumor microenvironment and activate cellular immunity. The future prospects may involve in the rational combination of a few immunotherapies for more efficient cancer inhibition and elimination.     

Engineering Macrophages for Cancer Immunotherapy and Drug Delivery

Macrophages play an important role in cancer development and metastasis. Proinflammatory M1 macrophages can phagocytose tumor cells, while anti-inflammatory M2 macrophages such as tumor-associated macrophages (TAMs) promote tumor growth and invasion. Modulating the tumor immune microenvironment through engineering macrophages is efficacious in tumor therapy. M1 macrophages target cancerous cells and, therefore, can be used as drug carriers for tumor therapy. Herein, the strategies to engineer macrophages for cancer immunotherapy, such as inhibition of macrophage recruitment, depletion of TAMs, reprograming of TAMs, and blocking of the CD47-SIRPα pathway, are discussed. Further, the recent advances in drug delivery using M1 macrophages, macrophage-derived exosomes, and macrophage-membrane-coated nanoparticles are elaborated. Overall, there is still significant room for development in macrophage-mediated immune modulation and macrophage-mediated drug delivery, which will further enhance current tumor therapies against various malignant solid tumors, including drug-resistant tumors and metastatic tumors.     

PD‐1 Blockade Cellular Vesicles for Cancer Immunotherapy

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.     

Cell-Based Drug Delivery Systems Participate in the Cancer Immunity Cycle for Improved Cancer Immunotherapy

Immunotherapy aims to activate the cancer patient's immune system for cancer therapy. The whole process of the immune system against cancer referred to as the “cancer immunity cycle”, gives insight into how drugs can be designed to affect every step of the anticancer immune response. Cancer immunotherapy such as immune checkpoint inhibitor (ICI) therapy, cancer vaccines, as well as small molecule modulators has been applied to fight various cancers. However, the effect of immunotherapy in clinical applications is still unsatisfactory due to the limited response rate and immune-related adverse events. Mounting evidence suggests that cell-based drug delivery systems (DDSs) with low immunogenicity, superior targeting, and prolonged circulation have great potential to improve the efficacy of cancer immunotherapy. Therefore, with the rapid development of cell-based DDSs, understanding their important roles in various stages of the cancer immunity cycle guides the better design of cell-based cancer immunotherapy. Herein, an overview of how cell-based DDSs participate in cancer immunotherapy at various stages is presented and an outlook on possible challenges of clinical translation and application in future development.     

MSN Anti‐Cancer Nanomedicines: Chemotherapy Enhancement,Overcoming of Drug Resistance,and Metastasis Inhibition

In the anti‐cancer war, there are three main obstacles resulting in high mortality and recurrence rate of cancers: the severe toxic side effect of anti‐cancer drugs to normal tissues due to the lack of tumor‐selectivity, the multi‐drug resistance (MDR) to free chemotherapeutic drugs and the deadly metastases of cancer cells. The development of state‐of‐art nanomedicines based on mesoporous silica nanoparticles (MSNs) is expected to overcome the above three main obstacles. In the view of the fast development of anti‐cancer strategy, this review highlights the most recent advances of MSN anti‐cancer nanomedicines in enhancing chemotherapeutic efficacy, overcoming the MDR and inhibiting metastasis. Furthermore, we give an outlook of the future development of MSNs‐based anti‐cancer nanomedicines, and propose several innovative and forward‐looking anti‐cancer strategies, including tumor tissue?cell?nuclear successionally targeted drug delivery strategy, tumor cell‐selective nuclear‐targeted drug delivery strategy, multi‐targeting and multi‐drug strategy, chemo‐/radio‐/photodynamic‐/ultrasound‐/thermo‐combined multi‐modal therapy by virtue of functionalized hollow/rattle‐structured MSNs.     

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.g., immune activator and immune inhibitor) and combination immunotherapy is reported herein. A library of stimuli-activatable BLPNs is fabricated yielding YES/AND logic outputs by adjusting the input combinations, including extracellular matrix metalloproteins 2/9 (MMP-2/9), intracellular acidity (pH = 5.0–6.0), and reduction (glutathione) in the tumor microenvironment. Tunable and selective control over BLPNs dissociation and prodrug activation is achieved by specifying the connectivity of orthogonal stimuli-labile spacers while exploiting the endogenous signals at the tumor sites. The tumor-specific distribution of the BLPNs and stimuli-activation of the immune modulators for highly efficient cancer immunotherapy are further demonstrated. The results reported in this study may open a new avenue for tumor-specific delivery of immune therapeutics and precise cancer immunotherapy.     

Materials for Immunotherapy

Breakthroughs in materials engineering have accelerated the progress of immunotherapy in preclinical studies. The interplay of chemistry and materials has resulted in improved loading, targeting, and release of immunomodulatory agents. An overview of the materials that are used to enable or improve the success of immunotherapies in preclinical studies is presented, from immunosuppressive to proinflammatory strategies, with particular emphasis on technologies poised for clinical translation. The materials are organized based on their characteristic length scale, whereby the enabling feature of each technology is organized by the structure of that material. For example, the mechanisms by which i) nanoscale materials can improve targeting and infiltration of immunomodulatory payloads into tissues and cells, ii) microscale materials can facilitate cell-mediated transport and serve as artificial antigen-presenting cells, and iii) macroscale materials can form the basis of artificial microenvironments to promote cell infiltration and reprogramming are discussed. As a step toward establishing a set of design rules for future immunotherapies, materials that intrinsically activate or suppress the immune system are reviewed. Finally, a brief outlook on the trajectory of these systems and how they may be improved to address unsolved challenges in cancer, infectious diseases, and autoimmunity is presented.     

T-Cell-Mimicking Nanoparticles for Cancer Immunotherapy

Cancer immunotherapies, including adoptive T cell transfer and immune checkpoint blockades, have recently shown considerable success in cancer treatment. Nevertheless, transferred T cells often become exhausted because of the immunosuppressive tumor microenvironment. Immune checkpoint blockades, in contrast, can reinvigorate the exhausted T cells; however, the therapeutic efficacy is modest in 70–80% of patients. To address some of the challenges faced by the current cancer treatments, here T-cell-membrane-coated nanoparticles (TCMNPs) are developed for cancer immunotherapy. Similar to cytotoxic T cells, TCMNPs can be targeted at tumors via T-cell-membrane-originated proteins and kill cancer cells by releasing anticancer molecules and inducing Fas-ligand-mediated apoptosis. Unlike cytotoxic T cells, TCMNPs are resistant to immunosuppressive molecules (e.g., transforming growth factor-β1 (TGF-β1)) and programmed death-ligand 1 (PD-L1) of cancer cells by scavenging TGF-β1 and PD-L1. Indeed, TCMNPs exhibit higher therapeutic efficacy than an immune checkpoint blockade in melanoma treatment. Furthermore, the anti-tumoral actions of TCMNPs are also demonstrated in the treatment of lung cancer in an antigen-nonspecific manner. Taken together, TCMNPs have a potential to improve the current cancer immunotherapy.     

A Dual Immunotherapy Nanoparticle Improves T‐Cell Activation and Cancer Immunotherapy

Combination immunotherapy has recently emerged as a powerful cancer treatment strategy. A promising treatment approach utilizes coadministration of antagonistic antibodies to block checkpoint inhibitor receptors, such as antiprogrammed cell death‐1 (aPD1), alongside agonistic antibodies to activate costimulatory receptors, such as antitumor necrosis factor receptor superfamily member 4 (aOX40). Optimal T‐cell activation is achieved when both immunomodulatory agents simultaneously engage T‐cells and promote synergistic proactivation signaling. However, standard administration of these therapeutics as free antibodies results in suboptimal T‐cell binding events, with only a subset of the T‐cells binding to both aPD1 and aOX40. Here, it is shown that precise spatiotemporal codelivery of aPD1 and aOX40 using nanoparticles (NP) (dual immunotherapy nanoparticles, DINP) results in improved T‐cell activation, enhanced therapeutic efficacy, and increased immunological memory. It is demonstrated that DINP elicits higher rates of T‐cell activation in vitro than free antibodies. Importantly, it is demonstrated in two tumor models that combination immunotherapy administered in the form of DINP is more effective than the same regimen administered as free antibodies. This work demonstrates a novel strategy to improve combination immunotherapy using nanotechnology.     

Stimulus-Responsive Drug Delivery Nanoplatforms for Osteoarthritis Therapy

Osteoarthritis (OA) is one of the most prevalent age-related degenerative diseases. With an increasingly aging global population, greater numbers of OA patients are providing clear economic and societal burdens. Surgical and pharmacological treatments are the most common and conventional therapeutic strategies for OA, but often fall considerably short of desired or optimal outcomes. With the development of stimulus-responsive nanoplatforms has come the potential for improved therapeutic strategies for OA. Enhanced control, longer retention time, higher loading rates, and increased sensitivity are among the potential benefits. This review summarizes the advanced application of stimulus-responsive drug delivery nanoplatforms for OA, categorized by either those that depend on endogenous stimulus (reactive oxygen species, pH, enzyme, and temperature), or those that depend on exogenous stimulus (near-infrared ray, ultrasound, magnetic fields). The opportunities, restrictions, and limitations related to these various drug delivery systems, or their combinations, are discussed in areas such as multi-functionality, image guidance, and multi-stimulus response. The remaining constraints and potential solutions that are represented by the clinical application of stimulus-responsive drug delivery nanoplatforms are finally summarized.     

Smart Nanosystems for Overcoming Multiple Biological Barriers in Cancer Nanomedicines Transport: Design Principles,Progress, and Challenges

The development of smart nanosystems, which could overcome diverse biological barriers of nanomedicine transport, has received intense scientific interest in improving the therapeutic efficacies of traditional nanomedicines. However, the reported nanosystems generally hold disparate structures and functions, and the knowledge of involved biological barriers is usually scattered. There is an imperative need for a summary of biological barriers and how these smart nanosystems conquer biological barriers, to guide the rational design of the new-generation nanomedicines. This review starts from the discussion of major biological barriers existing in nanomedicine transport, including blood circulation, tumoral accumulation and penetration, cellular uptake, drug release, and response. Design principles and recent progress of smart nanosystems in overcoming the biological barriers are overviewed. The designated physicochemical properties of nanosystems can dictate their functions in biological environments, such as protein absorption inhibition, tumor accumulation, penetration, cellular internalization, endosomal escape, and controlled release, as well as modulation of tumor cells and their resident tumor microenvironment. The challenges facing smart nanosystems on the road heading to clinical approval are discussed, followed by the proposals that could further advance the nanomedicine field. It is expected that this review will provide guidelines for the rational design of the new-generation nanomedicines for clinical use.     

Sequentially Site‐Specific Delivery of Apoptotic Protein and Tumor‐Suppressor Gene for Combination Cancer Therapy

Nanocarrier‐mediated codelivery of multiple anticancer drugs is a potential strategy for enhanced efficacy of combination cancer treatment by unifying differential pharmacokinetic properties and maintaining an optimal ratio of drug cargoes. However, a programmable codelivery system is highly desired to deliver different therapeutics to their specific sites of action to pursue maximized combinational effect. Herein a liposome‐based nanoassembly (p53/C‐rNC/L‐FA) is developed for intracellular site‐specific delivery of an apoptotic protein cytochrome c (CytoC) and a plasmid DNA encoding tumor‐suppressing p53 protein (p53 DNA). p53/C‐rNC/L‐FA consists of an acid‐activated fusogenic liposomal membrane shell modified with folic acid (L‐FA) and a DNA/protein complex core assembled by the p53 DNA, protamine and CytoC‐encapsulated redox‐responsive nanocapsule (C‐rNC). Intratumoral and intraendosomal acidities promote membrane fusion between liposome and biomembrane, resulting in release of the encapsulated p53/C‐rNC complex into the cytoplasm. The cytoplasmic reduction causes degradation of C‐rNC with release of CytoC that induces tumor cell apoptosis. The p53 DNA is transported into the nucleus by the aid of the cationic protamine and thus generates expression of the p53 protein that enhances apoptosis combined with CytoC. p53/C‐rNC/L‐FA is demonstrated to significantly induce tumor cell apoptosis and inhibit tumor growth in the orthotopic breast tumor mouse model.     

Nanomedicine‐Based Immunotherapy for the Treatment of Cancer Metastasis

Metastasis is the leading cause of cancer‐associated death, with poor prognosis even after extensive treatment. The dormancy of metastatic cancer cells during dissemination or after colony formation is one major reason for treatment failure, as most drugs target cells of active proliferation. Immunotherapy has shown great potential in cancer therapy because the activity of effector cells is less affected by the metabolic status of cancer cells. In addition, metastatic cells out of immunosuppressive tumor microenvironment (TME) are more susceptible to immune clearance, although these cells can achieve immune surveillance evasion via strategies such as platelet and macrophage recruitment. Since nanomaterials themselves or their carried drugs have the capability to modulate the immune system, a great amount of focus has been placed on nanomedicine strategies that leverage immune cells participating the metastatic cascade. These nanomedicines successfully inhibit the tumor metastasis and prolong the survival of model animals. Immune cells that are involved in the metastasis cascade are first summarized and then recent and inspiring strategies and nanomaterials in this growing field are highlighted.     

A Multistage Cooperative Nanoplatform Enables Intracellular Co-Delivery of Proteins and Chemotherapeutics for Cancer Therapy

Combining intracellularly active proteins with chemotherapeutics represents a promising strategy for synergistic cancer therapy. However, the lack of nanocarrier systems for delivery into cancer cells and controlled intracellular release of both physicochemically very distinct cargos significantly impedes the biomedical translation of this combination strategy in cancer therapy. Here, a well-designed triblock copolymer, mPEG-b-PGCA-b-PGTA, is reported for application in a multistage cooperative drug delivery nanoplatform that accomplishes effective intracellular co-delivery of hydrophilic ribonuclease A (RNase A) and hydrophobic doxorubicin (DOX). RNase A bioreversibly modified with phenylboronic acid groups via a ROS-cleavable carbamate linker is incorporated into the triblock copolymer nanoparticles with high efficiency through a pH-reversible phenylboronic acid–catechol linkage. The reversible covalent conjugations between RNase A and the triblock copolymer endow the nanoparticles with high stability under normal physiological conditions. Upon cellular internalization, the cooperative release of DOX and RNase A from the triblock copolymer nanoparticles is triggered at multiple stages by endosomal acidic environment and subsequent DOX-enhanced intracellular ROS environment. This leads to enhanced synergistic anticancer effects as demonstrated both in vitro and in vivo. Given the versatility of dynamic covalent conjugations, this work provides a universal and stable platform for intracellular co-delivery of various combinations of proteins and chemotherapeutics.