Nanotheranostics for the Management of Hepatic Ischemia-Reperfusion Injury.

Hepatic ischemia-reperfusion injury (IRI), in which an insufficient oxygen supply followed by reperfusion leads to an inflammatory network and oxidative stress in disease tissue to cause cell death, always occurs after liver transplantations and sections. Although pharmacological treatments favorably prevent or protect the liver against experimental IRI, there have been few successes in clinical applications for patient benefits because of the incomprehension of complicated IRI-induced signaling events as well as short blood circulation time, poor solubility, and severe side reactions of most antioxidants and anti-inflammatory drugs. Nanomaterials can achieve targeted delivery and controllable release of contrast agents and therapeutic drugs in desired hepatic IRI regions for enhanced imaging sensitivity and improved therapeutic effects, emerging as novel alternative approaches for hepatic IRI diagnosis and therapy. In this review, the application of nanotechnology is summarized in the management of hepatic IRI, including nanomaterial-assisted hepatic IRI diagnosis, nanoparticulate systems-mediated remission of reactive oxygen species-induced tissue injury, and nanoparticle-based targeted drug delivery systems for the alleviation of IRI-related inflammation. The current challenges and future perspectives of these nanoenabled strategies for hepatic IRI treatment are also discussed.

Multistage Adaptive Nanoparticle Overcomes Biological Barriers for Effective Chemotherapy.

Drug delivery systems (DDS) are extensively studied to improve the solubility, stability, pharmacokinetic, and biodistribution of chemotherapeutics. However, the drug delivery efficiency of traditional DDS is often limited by the complicated biological barriers in vivo. Herein, a multistage adaptive nanoparticle (MAN) that simultaneously overcomes multiple biological barriers to achieve tumor-targeted drug delivery with high efficiency is presented. MAN has a core-shell structure, in which both the core and the shell are made of responsive polymers. This structure allows MAN to present different surface properties to adapt to its surrounding biological microenvironment, thereby achieving enhanced stability in blood circulation, improved tumor accumulation and cellular internalization in tumor tissues, and effective release of drug in cells. With these unique characteristics, the MAN loaded with docetaxel achieves effective tumor suppression with reduced systemic toxicity. Furthermore, MAN can load almost any hydrophobic drugs, providing a general strategy for the tumor-targeted delivery of hydrophobic drugs to overcome the multiple biological barriers and improve the efficacy of chemotherapy.

NanoRNP Overcomes Tumor Heterogeneity in Cancer Treatment.

Tumor heterogeneity has been one of the most important factors leading to the failure of conventional cancer therapies due to the accumulation of genetically distinct tumor-cell subpopulations during the tumor development process. Due to the diversity of genetic mutations during tumor growth, combining the use of multiple drugs has only achieved limited success in combating heterogeneous tumors. Herein, we report a novel antitumor strategy that effectively addresses tumor heterogeneity by using a CRISPR/Cas9-based nanoRNP carrying a combination of sgRNAs. Such nanoRNP is synthesized from Cas9 ribonucleoprotein, any combinations of required sgRNAs, and a rationally designed responsive polymer that endows nanoRNP with high circulating stability, enhanced tumor accumulation, and the efficient gene editing in targeted tumor cells eventually. By carrying a combination of sgRNAs that targets STAT3 and RUNX1, the nanoRNP exhibited efficient gene expression disruptions on a heterogeneous tumor model with two subsets of cells whose proliferations were sensitive to the reduced expression of STAT3 and RUNX1, respectively, leading to the effective growth inhibition of the heterogeneous tumor. Considering the close relationship between tumor heterogeneity and cancer progression, resistance to therapy, and recurrences, nanoRNP provides a feasible strategy to overcome tumor heterogeneity in the development of more advanced cancer therapy against malignant tumors.

Nanocomposites Inhibit the Formation, Mitigate the Neurotoxicity, and Facilitate the Removal of ß-Amyloid Aggregates in Alzheimer's Disease Mice.

Alzheimer's disease (AD) is a progressive and irreversible brain disorder. Recent studies revealed the pivotal role of ß-amyloid (Aß) in AD. However, there is no conclusive indication that the existing therapeutic strategies exerted any effect on the mitigation of Aß-induced neurotoxicity and the elimination of Aß aggregates simultaneously in vivo. Herein, we developed a novel nanocomposite that can eliminate toxic Aß aggregates and mitigate Aß-induced neurotoxicity in AD mice. This nanocomposite was designed to be a small-sized particle (14 ± 4 nm) with Aß-binding peptides (KLVFF) integrated on the surface. The nanocomposite was prepared by wrapping a protein molecule with a cross-linked KLVFF-containing polymer layer synthesized by in situ polymerization. The presence of the nanocomposite remarkably changed the morphology of Aß aggregates, which led to the formation of Aß/nanocomposite coassembled nanoclusters instead of Aß oligomers. With the reduction of the pathological Aß oligomers, the nanocomposites attenuated the Aß-induced neuron damages, regained endocranial microglia's capability to phagocytose Aß, and eventually protected hippocampal neurons against apoptosis. Thus, we anticipate that the small-sized nanocomposite will potentially offer a feasible strategy in the development of novel AD treatments.

Spatial Confined Synergistic Enzymes with Enhanced Uricolytic Performance and Reduced Toxicity for Effective Gout Treatment.

Confinement of urate oxidase with detoxifying enzymes into multienzyme architecture is an appealing approach for gout treatment due to its capability to decompose serum uric acid without generation of H2 O2 . However, most of these strategies involve chemical modifications to the enzymes and barely consider enhancing the stability of the multienzyme architectures particularly against proteolysis, which significantly dampened its catalytic activity and in vivo stability. Herein, a novel strategy to prepare multienzyme nanoclusters with highly uricolytic activity and enhanced stability is demonstrated. With the close proximation, catalase can effectively decompose the H2 O2 generated by uricase during uricolysis. Moreover, with a shell structure constructed with polyethylene glycol, the nanocluster achieves great performance in reducing the nonspecific serum protein adsorptions and proteases digestion, leading to an enhanced circulation time after the intravenous administration. Such complementary multienzyme nanoclusters realize the long-term therapeutic effect in the management of serum uric acid level, without any toxicity or undesired immune responses in vivo. This work mimics the synergistic effect of protein complex in nature and can be further developed to a general method for the construction of multienzyme nanoclusters, which provides new opportunities for utilizing therapeutic enzymes for the treatment of metabolic diseases.

Nanofilamentous Virus-Based Dynamic Hydrogels with Tunable Internal Structures, Injectability, Self-Healing, and Sugar Responsiveness at Physiological pH.

With expanding applications of hydrogels in diverse fields ranging from biomaterials to sensors, actuators, and soft robotics, there is an urgent need to endow one single gel with multiple physicochemical properties, such as stimuli-responsiveness, injectability, self-healing, and tunable internal structures. However, it is challenging to simultaneously incorporate these highly sought-after properties into one single gel. Herein, a conceptual hydrogel system with all of these properties is presented via combining bioconjugate chemistry, filamentous viruses, and dynamic covalent bonds. Nanofilamentous bioconjugates with diol affinity were prepared by coupling a tailor-synthesized low-p Ka phenylboronic acid (PBA) derivative to a well-defined green nanofiber the M13 virus with a high aspect ratio (PBA-M13). Dynamic hydrogels with tunable mechanical strength were prepared by using multiple diol-containing agents such as poly(vinyl alcohol) to cross-link such PBA-M13 via the classic boronic-diol dynamic bonds. The as-prepared hydrogels exhibit excellent injectability and self-healing behaviors as well as easy chemical accessibility of the PBA moieties on the virus backbone inside the gel matrix. Ordered internal structures were imparted into virus-based hydrogels by simple shear-induced alignment of the virus nanofibers. Furthermore, unique hydrogels with chiral internal structures were fabricated through in situ gelation induced by diffusion of diol-containing molecules to fix the chiral liquid crystal phase of the PBA-M13 virus. Sugar responsiveness of this gel leads to a glucose-regulated release behavior of payloads such as insulin. All of these properties have been implemented at physiological pH, which will facilitate future applications of these hydrogels as biomaterials.

Self-Etching of Metal-Organic Framework Templates during Polydopamine Coating: Nonspherical Polydopamine Capsules and Potential Intracellular Trafficking of Metal Ions.

Traditionally, containers made from steel or other metals are not good for making tea, probably due to the fact that polyphenol components in tea can chelate with metal ions. A similar reason might stand behind the observations as reported herein. During the coating of well-defined metal-organic framework (MOF) crystalline particles with polydopamine (PDA) via pH-induced self-polymerization of dopamine, we found that MOF templates automatically etch off during the coating, giving rise to nonspherical PDA capsules that inherit the morphologies of the templates. Such self-etching of MOF templates is ascribed to the chelation of the metal nodes of the MOFs by the catechol moieties in the PDA layer. In addition, the self-etching of the zeolitic imidazolate framework-8 (ZIF-8) with a truncated cubic shape probably follows a crystalline facet-dependent fashion, resulting in intermediate yolk-shell structures with ZIF-8 cargos of various shapes inside a highly biocompatible PDA shell. Incubation of such intermediate hybrid particles with the cancerous HeLa cell line leads to pronounced cytotoxicity, which is tentatively connected with the cellular internalization of the ZIF@PDA nanoparticles because of the cell affinity of the PDA layer. Subsequently, the continuous release of Zn2+ by the self-etching of the encapsulated ZIF-8 inside the cell increases intracellular Zn2+ to a harmful level. Therefore, intracellular delivery of metal ions is probably realized, which might offer a novel way for cancer therapy.

GSH/pH dual responsive chitosan nanoparticles for reprogramming M2 macrophages and overcoming cancer chemoresistance.

The combination of two or more drugs with different mechanisms of action is a promising strategy for circumventing multidrug resistance (MDR). However, the antitumor effect of nanosystems is usually limited due to the simultaneous release of different payloads at a single location rather than at their respective sites of action. Herein, we report a GSH and pH dual responsive nanoplatform encapsulated with doxorubicin (DOX) and resiquimod (R848) (GPNP) for combinatorial chemotherapy against cancer cells with drug resistance. GPNP possesses a core-shell structure wherein the polymer shell detaches in the acidic and sialic acid (SA)-rich environment. This leads to the release of R848 into the tumor microenvironment (TME), thereby reprogramming M2 macrophages into M1 macrophages and exposing the core CS(DOX)-PBA to kill MCF-7/ADR cells. Additionally, the nitric oxide (NO) generated by M1 macrophages can suppress the P-glycoprotein (P-gp) expression to reduce the efflux of chemotherapy drugs, thus playing a combined role in overcoming MDR. In vitro studies have demonstrated the effectiveness of GPNP in reprogramming M2 macrophages and inducing apoptosis in MCF-7/ADR cells, resulting in enhanced antitumor efficacy. This work proposed an effective combination strategy to combat chemoresistance, providing new insights into the development of innovative combinatorial therapies against MDR tumors.

An antifouling membrane-fusogenic liposome for effective intracellular delivery in vivo.

The membrane-fusion-based internalization without lysosomal entrapment is advantageous for intracellular delivery over endocytosis. However, protein corona formed on the membrane-fusogenic liposome surface converts its membrane-fusion performance to lysosome-dependent endocytosis, causing poorer delivery efficiency in biological conditions. Herein, we develop an antifouling membrane-fusogenic liposome for effective intracellular delivery in vivo. Leveraging specific lipid composition at an optimized ratio, such antifouling membrane-fusogenic liposome facilitates fusion capacity even in protein-rich conditions, attributed to the copious zwitterionic phosphorylcholine groups for protein-adsorption resistance. Consequently, the antifouling membrane-fusogenic liposome demonstrates robust membrane-fusion-mediated delivery in the medium with up to 38% fetal bovine serum, outclassing two traditional membrane-fusogenic liposomes effective at 4% and 6% concentrations. When injected into mice, antifouling membrane-fusogenic liposomes can keep their membrane-fusion-transportation behaviors, thereby achieving efficient luciferase transfection and enhancing gene-editing-mediated viral inhibition. This study provides a promising tool for effective intracellular delivery under complex physiological environments, enlightening future nanomedicine design.

Spatiotemporal release of non-nucleotide STING agonist and AKT inhibitor from implantable 3D-printed scaffold for amplified cancer immunotherapy.

Immunotherapy through the activation of the stimulator of interferon genes (STING) signaling pathway is increasingly recognized for its robust anti-tumor efficacy. However, the effectiveness of STING activation is often compromised by inadequate anti-tumor immunity and a scarcity of primed immune cells in the tumor microenvironment. Herein, we design and fabricate a co-axial 3D-printed scaffold integrating a non-nucleotide STING agonist, SR-717, and an AKT inhibitor, MK-2206, in its respective shell and core layers, to synergistically enhance STING activation, thereby suppressing tumor recurrence and growth. SR-717 initiates the STING activation to enhance the phosphorylation of the factors along the STING pathway, while MK-2206 concurrently inhibits the AKT phosphorylation to facilitate the TBK1 phosphorylation of the STING pathway. The sequential and sustained release of SR-717 and MK-2206 from the scaffold results in a synergistic STING activation, demonstrating substantial anti-tumor efficacy across multiple tumor models. Furthermore, the scaffold promotes the recruitment and enrichment of activated dendritic cells and M1 macrophages, subsequently stimulating anti-tumor T cell activity, thereby amplifying the immunotherapeutic effect. This precise and synergistic activation of STING by the scaffold offers promising potential in tumor immunotherapy.

Structural and componential design: new strategies regulating the behavior of lipid-based nanoparticles in vivo.

Lipid-based nanoparticles have made a breakthrough in clinical disease as delivery systems due to their biocompatibility, thermal and long-term stability, high loading ability, simplicity of preparation, inexpensive production costs, and scalable manufacturing production. In particular, during the COVID-19 pandemic, this delivery system served as a vital vaccine component for virus confrontation. To obtain effective drug delivery, lipid-based nanoparticles should reach the desired sites with high efficiency, enter target cells, and release drugs. The structures and compositions of lipid-based nanoparticles can be modified to regulate these behaviors in vivo to enhance the therapeutic effects. Herein, we briefly review the development of lipid-based nanoparticles, from simple self-assembled nanovesicle-structured liposomes to multifunctional lipid nanoparticles. Subsequently, we summarize the strategies that regulate their tissue distribution, cell internalization, and drug release, highlighting the importance of the structural and componential design. We conclude with insights for further research to advance lipid-based nanotechnology.

Membrane-Fusion-Mediated Multiplex Engineering of Tumor Cell Surface Glycans for Enhanced NK Cell Therapy.

Natural killer (NK) cell therapies show potential for tumor treatment but are immunologically resisted by the overexpressed immunosuppressing tumor cell surface glycans. To reverse this glycan-mediated immunosuppression, the surface NK-inhibitory glycan expressions need to be downregulated and NK-activating glycan levels should be elevated synchronously with optimal efficiency. Here, a core-shell membrane-fusogenic liposome (MFL) is designed to simultaneously achieve the physical modification of NK-activating glycans and biological inhibition of immunosuppressing glycans on the tumor cell surface via a membrane-fusion manner. Loaded into a tumor-microenvironment-triggered-degradable thermosensitive hydrogel, MFLs could be conveniently injected and controllably released into local tumor. Through fusion with tumor cell membrane, the released MFLs could simultaneously deliver sialyltransferase-inhibitor-loaded core into cytoplasm, and anchor NK-activating-glycan-modified shell onto tumor surface. This spatially-differential distribution of core and shell in one cell ensures the effective inhibition of intracellular sialyltransferase to downregulate immunosuppressing sialic acid, and direct presentation of NK-activating Lewis X trisaccharide (LeX) on tumor surface simultaneously. Consequentially, the sialic acid-caused immunosuppression of tumor surface is reprogrammed to be LeX-induced NK activation, resulting in sensitive susceptibility to NK-cell-mediated recognition and lysis for improved tumor elimination. This MFL provides a novel platform for multiplex cell engineering and personalized regulation of intercellular interactions for enhanced cancer immunotherapy.

Anti-phagocytosis-blocking repolarization-resistant membrane-fusogenic liposome (ARMFUL) for adoptive cell immunotherapy.

Equipping multiple functionalities on adoptive effector cells is essential to overcome the complex immunological barriers in solid tumors for superior antitumor efficacy. However, current cell engineering technologies cannot endow these functionalities to cells within a single step because of the different spatial distributions of targets in one cell. Here, we present a core-shell anti-phagocytosis-blocking repolarization-resistant membrane-fusogenic liposome (ARMFUL) to achieve one-step multiplexing cell engineering for multifunctional cell construction. Through fusing with the M1 macrophage membrane, ARMFUL inserts an anti-CD47 (aCD47)-modified lipid shell onto the surface and simultaneously delivers colony-stimulating factor 1 receptor inhibitor BLZ945-loaded core into the cytoplasm. The surface-presenting aCD47 boosts macrophage's phagocytosis against the tumor by blocking CD47. The cytoplasm-located BLZ945 prompts its polarization resistance to M2 phenotype in the immunosuppressive microenvironment via inactivating the intracellular M2 polarization signaling pathway. This ARMFUL provides a versatile cell engineering platform to customize multimodal cellular functions for enhanced adoptive cell therapy.

A LIGHTFUL nanomedicine overcomes EGFR-mediated drug resistance for enhanced tyrosine-kinase-inhibitor-based hepatocellular carcinoma therapy.

Targeting the activated epidermal growth factor receptor (EGFR) via clustered regularly interspaced short palindromic repeat (CRISPR) technology is appealing to overcome the drug resistance of hepatocellular carcinoma (HCC) towards tyrosine kinase inhibitor (TKI) therapy. However, combining these two distinct drugs using traditional liposomes results in a suboptimal synergistic anti-HCC effect due to the limited CRISPR/Cas9 delivery efficiency caused by lysosomal entrapment after endocytosis. Herein, we developed a liver-targeting gene-hybridizing-TKI fusogenic liposome (LIGHTFUL) that can achieve high CRISPR/Cas9 expression to reverse the EGFR-mediated drug resistance for enhanced TKI-based HCC therapy efficiently. Coated with a galactose-modified membrane-fusogenic lipid layer, LIGHTFUL reached the targeting liver site to fuse with HCC tumor cells, directly and efficiently transporting interior CDK5- and PLK1-targeting CRISPR/Cas9 plasmids (pXG333-CPs) into the HCC cell cytoplasm and then the cell nucleus for efficient expression. Such membrane-fusion-mediated pXG333-CP delivery resulted in effective downregulation of both CDK5 and PLK1, sufficiently inactivating EGFR to improve the anti-HCC effects of the co-delivered TKI, lenvatinib. This membrane-fusion-participant codelivery strategy optimized the synergetic effect of CRISPR/Cas9 and TKI combinational therapy as indicated by the 0.35 combination index in vitro and the dramatic reduction of subcutaneous and orthotopic TKI-insensitive HCC tumor growth in mice. Therefore, the established LIGHTFUL provides a unique co-delivery platform to combine gene editing and TKI therapies for enhanced synergetic therapy.

Membrane-fusogenic biomimetic particles: a new bioengineering tool learned from nature.

Membrane fusion, a fundamental biological process of the fusion of the membrane composition between cells, is vital for cell-cell communication and cargo transport between living cells. This fusion interaction achieves the transportation of the inner content to the cellular cytosol as well as the simultaneous blending of foreign substances with the cell membrane. Inspired by this biological process, emerging membrane-fusogenic particles have been developed, opening a new area for bioengineering and biomedical applications. Especially, membrane-fusion-mediated transfer of inner cargoes can bypass endosomal entrapment to maximize the transportation efficiency, emerging as a unique cytoplasmic delivery platform distinct from those depending on conventional endocytosis-based pathways. In addition, the membrane fusion enables cell surface modification through lipid diffusion and mixing, providing a tool for direct cell membrane engineering. In this review, we focus on the development of membrane-fusogenic particles and their up-to-date progress. We briefly introduce the concept of membrane fusion, elaborate inspiring strategies of membrane-fusogenic particles, and highlight the recent advances and the promising applications of membrane-fusogenic particles as a next-generation bioengineering tool. In the end, we conclude with the present challenges and opportunities, providing insights in the future research of membrane-fusogenic particles.

Recent advances in nanomaterials for prostate cancer detection and diagnosis.

Despite the significant progress in the discovery of biomarkers and the exploitation of technologies for prostate cancer (PCa) detection and diagnosis, the initial screening of these PCa-related biomarkers using current technologies is always demanded with a bioassay or probe with high sensitivity, specificity, and noninvasiveness. Nanomaterials have emerged as novel alternative probes for PCa detection and diagnosis because of their nanoscale size, large ratio of surface area to volume, special surface chemistry, and particularly distinct physical properties. By selecting appropriate nanomaterials, a series of nanosensors or nanoprobes could be constructed for PCa bioassay with high sensitivity, selectivity, and accuracy. Meanwhile, nanosized particles also show significant potential to transport directors or contrast agents to desired sites in vivo for accurate and safe visualization of PCa tissues. Based on these advancements, this review will first outline the recent exploration of PCa biomarkers and the development of technologies for clinical PCa diagnosis. Then, the commonly used nanomaterials for PCa detection and diagnosis will be summarized. Finally, the current challenges and prospects of nanoparticle-based PCa detection and diagnosis methods are also discussed.

Engineering Nano-Therapeutics to Boost Adoptive Cell Therapy for Cancer Treatment.

Although adoptive transfer of therapeutic cells to cancer patients is demonstrated with great success and fortunately approved for the treatment of leukemia and B-cell lymphoma, potential issues, including the unclear mechanism, complicated procedures, unfavorable therapeutic efficacy for solid tumors, and side effects, still hinder its extensive applications. The explosion of nanotechnology recently has led to advanced development of novel strategies to address these challenges, facilitating the design of nano-therapeutics to improve adoptive cell therapy (ACT) for cancer treatment. In this review, the emerging nano-enabled approaches, that design multiscale artificial antigen-presenting cells for cell proliferation and stimulation in vitro, promote the transducing efficiency of tumor-targeting domains, engineer therapeutic cells for in vivo imaging, tumor infiltration, and in vivo functional sustainability, as well as generate tumoricidal T cells in vivo, are summarized. Meanwhile, the current challenges and future perspectives of the nanostrategy-based ACT for cancer treatment are also discussed in the end.

Coexistence of a new type of bound state in the continuum and a lasing threshold mode induced by PT symmetry.

Some photonic systems support bound states in the continuum (BICs) that have infinite lifetimes, although their frequencies and momenta are matched to vacuum modes. Using a prototypical system that can be treated analytically, we show that each of these BICs always splits into a pair of new type BIC and lasing threshold mode when a parity-time (PT)-symmetric perturbation is introduced. The radiation loss at the lasing threshold is exactly balanced by the net gain of the particles. These PT symmetry-induced BICs are different from ordinary BICs, as they can be excited by an external source but do not radiate, and they carry a different quality factor divergence rate from that of the ordinary BICs. While most of the attention of PT-symmetric systems is captured by the coalescence of modes at exceptional points, the splitting of ordinary BICs is a new phenomenon that illustrates the rich physics embedded in PT-symmetric systems.

Oral delivery of bacteria: Basic principles and biomedical applications.

Bacterial therapy, which presents a smart platform for delivering and producing therapeutic agents, as monotherapy or in combination with other therapeutic modes, has provided a breakthrough for the treatment of a range of diseases. The integration of synthetic biology technology with bacteria enables their characteristics like chemotaxis and biomolecule secretion to outperform conventional diagnostics and therapeutics, thereby facilitating their clinical applications in a range of diseases. Compared to injection-administered bacteria, orally-delivered bacteria improve patient compliance while avoiding the risk of systemic infections. However, oral administration of microbes always leads to a substantial loss of viability due to the highly acidic environment in the stomach and bile salt in the intestine. Thus, the formulation of these bacteria into microcapsules using appropriate biomaterials is a promising approach for reducing cell death during gastrointestinal passage and controlling the release of these therapeutic cells across the intestinal tract. In this review, we reveal the basic principles of oral bacterial delivery, from internal genetic engineering approaches to external encapsulation and modification, and summarize the most recent biomedical applications. Finally, we discuss future trends in oral bacterial therapy as well as current challenges that need to be resolved to advance their clinical applications.

Multifunctional Nanomodulators Regulate Multiple Pathways To Enhance Antitumor Immunity.

Immunosuppression is a key factor leading to a low therapeutic efficiency of the currently used immunotherapies. Monotherapies are unable to overcome immunosuppression because of the complex interplay of immune cells in tumors. Herein, we report a multifunctional nanomodulator (MFNM) as a carrier to deliver different types of immune modulators for comodulating multiple pathways. An MFNM has a core-shell structure, in which small-molecule drugs are encapsulated in a mesoporous silica nanoparticle (MSN) core with a pH-responsive polymer layer. Further, the polymeric shell provides active sites that are readily modifiable by multiple types of antibodies to regulate the immune-related processes. By codelivering cyclophosphamide (CTX), αPD-L1 (B7-H1), and α4-1BB (CD137L) monoclonal antibodies (mAbs) to tumors, an MFNM has been shown to regulate multiple immune pathways and enhance an antitumor immunity. As antibodies and small-molecule drugs loaded in an MFNM can be modified based on the tumor type, the MFNM provides a feasible platform for the development of advanced immunotherapies that require simultaneous modulation of multiple biological processes.