Application of nanomedicines in tumor immunotherapy

Abstract

Tumor immunotherapy has emerged as a formidable strategy, demonstrating substantial achievements in the field of cancer treatment. Despite its remarkable success, intrinsic limitations such as insufficient targeting capabilities, side effects, and resistance to immunotherapy hinder its efficacy. To address these challenges, the utilization of nanomedicines in tumor immunotherapy has been broadly explored, capitalizing on their advantages of targeting delivery capability, loading capacity, modifiability, and biocompatibility. Through rational design approaches, nanomedicines are engineered to meet diverse delivery requirements and synergize with different regimens to maximize therapeutic efficacy while alleviating side effects. This review initially discusses the challenges associated with tumor immunotherapy and underscores the pivotal role played by nanomedicines in overcoming these obstacles. Subsequently, representative types of nanoparticles are systematically introduced based on their structural properties, advantages, potential limitations, and future research directions. Special emphasis is placed on recent advancements in a range of nanomedicines designed for specific tumor immunotherapy strategies. Finally, the clinical applications as well as prospects of nanomedicines are discussed.

Introduction

Tumor immunotherapy represents a promising strategy that aims to stimulate patients’ antitumor immune response for tumor recognition and eradication while also establishing long-term immunological memory to prevent metastasis and recurrence (Kennedy and Salama, 2020). The main categories of immunotherapy encompass immune checkpoint blockades (ICBs), monoclonal antibody (mAb) therapy, tumor vaccines, adoptive cell transfer (ACT), cytokine therapy, oncolytic virus (OV) immunotherapy, and immune combination therapy (Koyande et al., 2022). In comparison to conventional therapeutic modalities for cancer, immunotherapy offers distinct advantages due to its prolonged treatment duration, relatively mild side effects, and favorable efficacy. However, several obstacles still hinder clinical effectiveness. Firstly, inadequate targeting capabilities and limited penetrability through physiological barriers within tumor tissues impede the efficient delivery of immunoregulatory drugs and tumor vaccines (Wang et al., 2022c). Secondly, inflammatory toxicities associated with tumor immunotherapy restrict its clinical applications. For instance, checkpoint blockade toxicity can invade peripheral organs characterized by significant variability and unpredictability due to T-cell hyperreactivity (Khan and Gerber, 2020; Waldman et al., 2020). Finally, primary resistance and acquired resistance to immunotherapy can result in a low immune response clinically (O’Donnell et al., 2019). Notably, primary resistance to anti-programmed cell death-1 (anti-PD1) therapies has been observed in ∼60% of melanoma patients, while acquired resistance has been documented in ∼25% of patients (Topalian et al., 2012; Ribas et al., 2016). Therefore, it is imperative to explore approaches for addressing the aforementioned limitations of tumor immunotherapy.

Nanoparticles (NPs) refer to heterologous small composites typically ranging in size from 1 nm to 100 nm. They can occur naturally such as exosomes, or be artificially synthesized from various materials through nanotechnology. NPs can be categorized into lipid-based, polymer-based, inorganic, biomimetic, and hybrid NPs based on their components. These diverse NPs show promise in optimizing tumor immunotherapy and overcoming existing limitations (Namiot et al., 2023). Owning to the specific scale, NPs can passively traverse through enlarged inter-endothelial gaps of leaky vascular structures and selectively accumulate in tumor tissue (Hobbs et al., 1998; Kalyane et al., 2019). This phenomenon is known as the enhanced permeability and retention (EPR) effect, which allows for passive targeting of antitumor therapeutic cargo-bearing NPs with enhanced intratumoral accumulation, reduced nonspecific uptake, and improved efficacy (Figure 1A). Furthermore, the incorporation of ligand modification such as antibodies, peptides, aptamers, and polysaccharides as well as small molecules confers active targeting capability to NPs for precise action at specific sites (Qian et al., 2019; Yoo et al., 2019; Zhang et al., 2019b; Cho et al., 2020; Yang et al., 2023; Bai et al., 2024), making them suitable for different modalities of immunotherapy such as direct killing of tumor cells, remodelling of tumor microenvironment (TME), and immune activation (Figure 1B; Arranja et al., 2017; Kim et al., 2021; Yang et al., 2021a). In addition to targeted delivery, NPs improve the properties of medicines by improving stability, prolonging circulation time, and promoting specific cellular uptake, which amplifies therapeutic efficacy while minimizing adverse effects (Figure 1C ; Gowd et al., 2022; Katopodi et al., 2022). Moreover, the sophisticated design of NPs is beneficial in orchestrating immune combination therapy in a spatiotemporally controlled manner, thereby demonstrating their potential to overcome the resistance to cancer immunotherapy (Zhu et al., 2021; Figure 1D).

Figure 1.

Schematic diagram of the characteristics of NPs in promoting tumor immunotherapy. (A) EPR effect facilitates passive targeting of NPs to tumor regions, thereby promoting the accumulation of anticancer drugs. (B) Ligand modification broadens the applicability of NPs for delivering drugs to various action sites, enabling direct eradication of tumor cells, TME remodelling, and immune activation. (C) NPs improve drug characteristics by enhancing stability and prolonging circulation time while also facilitating specific cellular uptake to enhance efficacy. (D) Through sophisticated design, NPs mediate a diverse range of therapies such as chemotherapy, radiotherapy, photothermal therapy, and photodynamic therapy in coordination with tumor immunotherapy. The induction of ICD contributes to reversing the immunosuppressive TME and strengthening immune responses synergistically. NIR, near-infrared ray. This figure is created with BioRender.com.

The application of nanotechnology in tumor immunotherapy holds significant promise and potential. Ongoing research endeavors are dedicated to the development of innovative nanomedicines, alongside advancing clinical trials. However, there are some limitations that need to be overcome for their successful implementation. For example, the absence of a comprehensive evaluation regarding potential interactions between nanomedicines and the biological environment, as well as their intricate composition, may give rise to safety concerns (Dormont et al., 2019; Stater et al., 2021). The scale-up manufacturing of nanomedicines poses challenges for ensuring reproducibility of physicochemical characteristics, which is crucial for maintaining their overall performance in vivo (Younis et al., 2022). Therefore, a comprehensive review of the application of nanomedicine in tumor immunotherapy can provide valuable insights for innovative development in preclinical studies and facilitate clinical translation of nanomedicines with enhanced characteristics. This review presents various types of NPs along with their potential limits and discusses the future research directions. Special emphasis is given to the advancements in nanomedicine for tumor immunotherapy. Furthermore, we provide an overview of the current clinical landscape of nanomedicines and outline prospects.

Types of NPs

NPs are heterologous small composites typically ranging in size from 1 nm to 100 nm (Namiot et al., 2023). They can be crafted from diverse materials, including lipids, polymers, and inorganic materials, and may also be derived from natural substances such as self-assembling proteins and exosomes. NPs are commonly categorized into lipid-based NPs, polymer-based NPs, inorganic NPs (iNPs), biomimetic NPs, and hybrid NPs (Figure 2). In this section, we provide an overview of NP classification along with their distinctive properties.

Figure 2.

Schematic diagram of representative types of NPs. Based on the materials utilized, NPs can be categorized into lipid-based, polymer-based, inorganic, biomimetic, and hybrid NPs. Specifically, biomimetic NPs are characterized by their composition of natural macromolecular components. Hybrid NPs are defined as particles composed of at least two constituents. This figure is created with BioRender.com.

Lipid-based NPs

Lipid-based NPs typically present a spherical structure comprising an outer lipid layer and an inner aqueous compartment, while containing various subset structures (Mitchell et al., 2021). Lipid-based NPs offer advantages including robust cellular uptake properties, surface modification flexibility, favorable biocompatibility, and enhanced bioavailability (Kumar et al., 2022). Besides, the lipid formulations are facile to adjust to improve delivery efficiency, increase medication availability, and evade immune system detection (Sheoran et al., 2022). Representative categories of lipid-based NPs include liposomes, micelles, and solid lipid nanoparticles (SLNs).

Liposomes refer to spherical vesicles derived from the self-assembly of amphiphilic lipid molecules in solution, structurally comprising one or more lipid bilayers. They possess stability, high load capacity, biodegradability, and biocompatibility, rendering them available for the delivery of molecules with varying polarities (Guimaraes et al., 2021). The majority of Food and Drug Administration (FDA)-approved nanomedicines for tumor treatment belong to liposomal formulations, such as Doxil, Marqibo, and Onivyde. Liposomes can be subdivided into cationic and anionic types in terms of their surface charge properties. Cationic liposomes can promote cell association, uptake, lysosomal escape, and nucleic acid concentration efficiently, making them widely utilized as optimal carriers for mRNA vaccines (Li et al., 2022c). Conversely, owing to the electrostatic repulsion, anionic liposomes enable reduced nonspecific cell uptake to alleviate cytotoxicity and prolonged circulation in the bloodstream (Large et al., 2021). Based on the aforementioned characteristics, liposomes have extensive applications in tumor immunotherapy.

Phospholipid micelles, self-assembled by amphiphilic molecules above the critical micelle concentration, exhibit distinct structures where the hydrophobic domains aggregate and face away from the aqueous environment, while the hydrophilic domains orient towards water (Feng and Mumper, 2013). They offer the advantages of convenient and reproducible preparation procedures and long-term storage through lyophilization. In terms of drug delivery, they are primarily employed for hydrophobic drug administration while being limited by their small interior hydrophobic space (Banerjee and Onyuksel, 2012). Furthermore, the conjugation of hydrophilic drugs to micelles results in increased lipophilicity and enhanced membrane permeability (Zielinska et al., 2022).

SLNs are spherical vesicles consisting of inner solid lipid and surrounding layers of surfactants as stabilizers, which effectively restrict the mobility of molecules within the lipid matrix and coalescence of NPs (Mirchandani et al., 2021; Zhang et al., 2023d). Surfactants play a pivotal role in polymorphic transitions of lipid core, usually contributing to a more efficient stabilization of SLNs (De Jesus and Zuhorn, 2015). In comparison to other lipid-based NPs, SLNs demonstrate superior physical stability by minimizing drug leakage and burst release, enabling controlled release. Furthermore, the synthesis methods for SLNs without organic solvents not only ensure lower toxicity in the final production but also facilitate convenient large-scale manufacturing (Tenchov et al., 2021).

As one of the most widely utilized types of NPs, there is an urgent necessity for the development of lipid-based NPs in order to establish a more universally applicable method to meet the gradually increasing application requirements, such as organ targeting, payload capacity, safety, dispersive stability, and responsive release. Although additional modifications can enhance the properties of lipid-based NPs, they simultaneously present challenges in terms of toxicity evaluation, scalable production, storage stability, and maintenance of in vivo performance, thereby hindering their widespread clinical application. The adjustment of lipid composition has been increasingly emphasized by recent research due to its feasibility, simplicity, and versatility. Therefore, further investigation into the correlation between lipid structure and biological function is essential for systematically optimizing lipid composition and proportion. Moreover, the introduction of a wider range of artificially synthesized lipid molecules with diverse chemical structures into lipid-based NPs is anticipated, as they have the potential to enhance properties even further.

Polymer-based NPs

Polymer-based NPs are derived from natural or synthetic polymers, encompassing a diverse range of structures, including polymer micelles, polymersomes, dendrimers, and polymeric NPs (Ferrari et al., 2018; Lu et al., 2021; Dong et al., 2024). Natural polymer materials have been widely employed for the synthesis of NPs due to their biocompatibility, biodegradability, non-immunogenicity, and cost-effectiveness (Fazal et al., 2023). Synthetic polymers like poly(ethylene glycol) (PEG), poly(lactic acid) (PLA), and poly(lactic glycolic acid) (PLGA) possess diverse chemical functional groups that offer advantages in terms of easy modification, self-assembling ability, and stimuli-responsiveness based on the presence of sensitive groups and bonds such as tertiary amine groups, acetal bonds, and disulfide bonds (Mukerabigwi et al., 2019; Wang et al., 2022c). Compared to lipid-based NPs, natural and synthetic polymer-based NPs offer the advantages of diverse composition, facile preparation, and functionalization, as well as stability. As a result, polymer-based NPs play a crucial role in intelligent delivery systems, thereby enabling controlled release in response to different pathological stimuli. However, it is noteworthy that stimulus-responsive polymer-based NPs, despite their attractive traits, have been barely tested in clinical trials, which may be attributed to concerns regarding their unstable performance, potential toxicity risks, and challenges associated with scaling up production. Therefore, it is crucial to consider product reproducibility and cost-effectiveness during the preclinical stage design as well as long-term evaluation of safety and stable efficacy in the clinical stage (Javia et al., 2022).

iNPs

iNPs, as a general term, refer to NPs fabricated from a wide array of inorganic materials such as gold, silicon, carbon, iron oxide, and quantum dots. They offer advantages including long-term stability, high surface-to-volume ratio, favorable uniformity, and intrinsic immunogenicity (Hess et al., 2019). In contrast to organic NPs, iNPs possess distinctive optical, electrical, thermal, ultrasonic, and magnetic properties generally, which enable their utilization in cancer diagnosis and imaging. Additionally, they can be used for direct antitumor modalities involving photothermal therapy (PTT) and photodynamic therapy (PDT), as well as combination therapies (Wang et al., 2021a; Zhang et al., 2023a). Representative iNPs incorporate metallic NPs, mesoporous silica NPs (MSNs), and carbon nanotubes (CNTs).

Metallic NPs refer to NPs derived from metals such as gold, silver, iron, and their oxides, exhibiting advantages including high density to promote cell uptake and precise manipulation of size, shape, charge, and surface modification (Evans et al., 2018). Bare gold nanoparticles have been certified to activate immunity and possess intrinsic antitumor capabilities via signaling blockade, rendering them suitable carriers for tumor immunotherapy (Bawage et al., 2016; Saha et al., 2016). Iron NPs are widely utilized as cancer theranostic agents due to their stability, prolonged half-life, and favorable biodistribution (Fernandes, 2023). Additionally, iron NPs exhibit magnetic properties for facilitating magnetic navigation and magnetic hyperthermia, which can enhance immunotherapy (Cheng et al., 2021).

MSNs are distinguished by their large surface areas and porous structures, which confer upon them biodegradability, low toxicity, high loading capacity, and the ability to regulate antigen delivery (García-Fernández et al., 2021). MSNs with larger pore sizes have demonstrated superior efficiency in antigen cross-presentation, reduced production of reactive oxygen species (ROS), faster degradation, and enhanced rates of drug release (Hong et al., 2020). The hydroxyl moieties on the surfaces of MSNs provide numerous sites for facile chemical functionalization to achieve controlled cargo release (Tran et al., 2018; Kankala et al., 2022).

CNTs are synthesized from the rolling of graphene sheets to form tubular and fiber-like structures, which can be further categorized as single-walled and multi-walled varieties based on the arrangement of graphene sheets (Sheikhpour et al., 2020). The exceptional properties of CNTs, such as their high surface area-to-volume ratio, flexible surface chemistry, high drug-loading capacity, and chemical stability, render them highly desirable carriers (Raphey et al., 2019). Moreover, their capability to be internalized through diverse mechanisms, broadly classified into endocytosis and passive diffusion, makes them particularly suitable for application in immunotherapy (Zare et al., 2021). Surface functionalization is usually exploited to enhance cellular uptake of CNTs, and their intrinsic shortcomings, such as poor dispersibility and tendency to aggregate, thereby reducing cytotoxicity (Zhang et al., 2015; Mei et al., 2018).

The safety issue of iNPs remains a major challenge in the field of nanomedicine owing to their complex interaction with the biological environment. Studies have indicated that iNPs, such as Fe₂O₃ NPs, TiO₂ NPs, and Ag NPs, have the potential to induce oxidative stress, biochemical disruption, and genotoxicity (Rizk et al., 2017; Lu et al., 2022; Siddiqui et al., 2023). Moreover, in a study conducted by Peng et al. (2019), iNPs encompassing titanium dioxide, silica, and gold have been proven to cause gaps between endothelial cells, ultimately accelerating the metastasis and promoting the generation of new metastasis sites of breast cancer cells (Peng et al., 2019). The current primary research direction to overcome this challenge involves conducting comprehensive toxicological assessments over the long term, encompassing biodistribution, biological interaction, metabolism, cytotoxicity, and adverse immune stimulation in both in vitro and in vivo settings (Czarnecka et al., 2020; Li et al., 2024b). Additionally, an effective strategy to prevent the detrimental interaction of iNPs with the biological environment and alleviate potential toxicity is by incorporating surface chemistry modulation (Mahamuni-Badiger and Dhanavade, 2023).

Biomimetic NPs

Exogenous NPs are susceptible to the formation of protein corona and undesirable interaction with biological systems (Vijayan et al., 2019). Biomimetic NPs have been engineered to improve the characteristics of synthetic NPs, enhance colloidal stability, prolong circulation time, and mitigate the risk of off-target accumulation and adverse reactions in the complex in vivo environment following administration (Soprano et al., 2022). This section provides an overview of biomimetic NPs, including virus-like particles (VLPs), self-assembling protein NPs, cell membrane-coated NPs, and extracellular vesicles (EVs).

VLPs

VLPs are naturally occurring or artificially designed symmetrical nanostructures formed by self-assembled viral proteins, devoid of viral genetic material. These VLPs serve as a protective and slightly flexible shell for therapeutic cargo, demonstrating biocompatibility, safety, biodegradability, and favorable immunogenicity (He et al., 2022). The structural and functional similarities to viruses confer an inherent affinity of VLPs for specific cellular receptors and host cell entry mechanisms, making them ideal carriers for intracellular delivery (Shan et al., 2023). In addition, the uniform size and defined chemistry of VLPs contribute to the consistent accumulation of cargo and surface modification (Ikwuagwu and Tullman-Ercek, 2022). Leveraging genetic engineering and chemical modification, VLPs present a degree of flexibility in physicochemical properties, which can be tailored for various cargos including chemical drugs, genetic drugs, peptides, and proteins (Chen et al., 2023).

Self-assembling protein NPs

Self-assembling protein NPs are defined as organized aggregated peptidic NPs formed through self-assembly in response to exposure to external stimuli (Pugliese and Gelain, 2017). Ferritin, which plays a crucial role in iron metabolism and homeostasis in organisms, possesses a hollow and spherical nanostructure derived from self-assembled subunits (Mohanty et al., 2022). Due to its H-chain, ferritin exhibits a specific affinity for the transferrin-1 receptor, which is frequently overexpressed on cancer cells, making ferritin an effective carrier for cancer treatment (Obozina et al., 2023). Vault NPs refer to the self-assembling ribonucleoprotein complex comprising 78 copies of major vault protein, demonstrating a symmetrical, barrel-like, hollow structure (Frascotti et al., 2021). These NPs offer several advantages such as favorable size, non-immunogenicity, sufficient interior space, and biodegradability (Rome and Kickhoefer, 2013). Albumin demonstrates an extended half-life and an inherent propensity to accumulate at tumor sites characterized by poor lymphatic drainage, subsequently being preferentially internalized by tumor cells with high metabolic demands (Hoogenboezem and Duvall, 2018). It is noteworthy that, in 2020, an albumin fusion protein was engineered to incorporate Arg–Gly–Asp (RGD) peptide, enzyme digestion sequence, and polyhistidine. This design endowed the protein with the capability to self-assemble into NPs based on the hydrophobicity of polyhistidine (Wang et al., 2020b). These NPs exhibited active targeting capability and facilitated tumor penetration and lysosomal escape by responding to matrix metalloproteinase (MMP)-2 enzyme cleavage and transforming into small histidine micelles.

Cell membrane-coated NPs

The cell membrane coating strategy aims to camouflage NPs with natural cell membranes, allowing these NPs to inherit the natural bio-interfacing properties of the source cells. By leveraging the complex surface architecture and multiple signals of the cell membranes, these cell membrane-coated NPs are capable of concealing exogenous features, evading immune clearance, and traversing diverse biological barriers (Liu et al., 2021). Furthermore, membrane coating can also serve as antigen sources or transfer immunostimulatory signals for immunotherapy, depending on the type of membrane. Additionally, these cell membrane-coated NPs can be further fine-tuned through genetic and metabolic engineering of the source membrane (Fang et al., 2023b). In this section, we will introduce characteristics of several different cell membrane-coated NPs synthesized from those including platelets, cancer cells, red blood cells (RBCs), white blood cells (WBCs), and bacteria.

Platelets confer natural pathophysiological affinity to NPs for tumor cells due to the protein profile expressed on their membrane surface. The efficient interaction between platelet membrane-coated NPs and tumor cells results in prolonged tissue persistence, enhanced efficacy of anticancer drugs, and extended duration of immune memory (Bahmani et al., 2021). In addition, the presence of the cluster of differentiation 47 (CD47) on the platelet membrane can augment the immune evasion capability of NP cores and prolong circulation by interacting with signal regulatory proteins on immune cells (Han et al., 2022).

The membranes of cancer cells possess the capability to facilitate robust homotypic targeting of NPs and prevent the formation of protein coronas due to the presence of receptors on the membranes. Furthermore, antigens and proteins such as CD47 and CD24 can independently contribute to activating antitumor immune responses and promoting the immune evasion of NPs (Lin et al., 2023). Therefore, the coating of cancer cell membranes offers numerous advantages, such as efficient homologous targeting, biocompatibility, prolonged half-life, and enhanced immunogenicity. In a study conducted by Chen et al. (2021a), it was demonstrated that cancer cell membrane-coated polymer NPs displayed an impressive intracellular uptake rate of 61.67% in vitro, along with superior active targeting capabilities and efficient in vivo accumulation, ultimately contributing to enhanced therapeutic efficacy of loaded drugs. Furthermore, it was observed that cancer cell membrane-coated NPs were able to disrupt the migration of cancer cells towards fibroblasts and reduce metastasis (Jin et al., 2019).

The coating of NPs with RBC membranes results in reduced clearance by the reticuloendothelial system, enhanced colloidal stability, extended blood circulation, and improved tumor accumulation (Li et al., 2022b). Additionally, the extraction and purification process of RBC membranes is simplified due to the absence of a nucleus and organelles (Xia et al., 2019). In a groundbreaking approach, modification of RBC membranes with anti-low-density lipoprotein receptor antibodies not only preserves the aforementioned advantages but also confers NPs with potent hypoxic tumor targeting, improved cellular uptake, and significant enrichment in tumor sites (Pan et al., 2022b).

WBCs, functioning as immune cells, possess the capability to detect and respond to pathogens and immune signals, while also naturally homing in on disease sites through cellular surface ligands. Furthermore, the membranes of WBCs enable NP cores to evade phagocytosis by self-recognition with source cells (Wang et al., 2022b). As a result, WBC-coated NPs demonstrate spontaneous tumor targeting, prolonged circulation time, and enhanced accumulation in tumor tissues (Jun et al., 2020).

Bacterial membranes, which display pathogen-associated molecular patterns, can impart NPs with inherent adjuvant properties to stimulate innate immunity and promote adaptive immune responses (Soprano et al., 2022; Zhao et al., 2022b). Additionally, proteins can be readily presented on the bacterial membrane surface through genetic manipulation.

EVs

EVs refer to membrane-enclosed vesicles secreted from cells, which play a crucial role in mediating intracellular communication by packaging a diverse array of signaling molecules. It has been revealed that EVs exhibit significant heterogeneity in their biogenesis, physical characteristics, and content composition, widely involved in the maintenance of cellular homeostasis and regulation of disease progression (Huang et al., 2020a). Importantly, the complex surface proteins and molecular cargo associated with their source cells endow EVs with targeted delivery capacity, enhanced stability during circulation, favorable biocompatibility, and immunoregulatory capability (Tran et al., 2015; Kimiz-Gebologlu and Oncel, 2022; Buzas, 2023). Consequently, EVs have been extensively manipulated for use as delivery systems and therapeutic agents.

According to their biogenesis, EVs are broadly categorized into ectosomes, which originate from the outward budding of the plasma membrane, and exosomes, which are generated by the inward budding of endosomes (Jeppesen et al., 2023). The production of ectosomes has been improved to specifically encapsulate endogenous bioactive molecules leveraging the split green fluorescent protein complementary system, thereby achieving efficient macromolecular delivery and genome modification (Zhang et al., 2020). Exosomes have been extensively engineered for use as tumor vaccines. Tumor-derived exosomes carrying tumor antigens have been demonstrated to elicit potent dendritic cell (DC)-mediated immune responses and reduce the population of regulatory T cells (Tregs) (Wang et al., 2020a). Mature DC-derived exosomes, which retain antigenic peptide–major histocompatibility complex (pMHC) and co-stimulatory molecules from parental DCs, enabling them to directly prime T cells (Lee et al., 2023), are considered promising cell-free DC vaccines with improved penetrating capability, reduced susceptibility to immunosuppressive molecules, enhanced stability during storage, and increased efficiency in activating T and natural killing cells (Luo et al., 2023).

The incorporation of natural biological components, such as proteins and membranes, confers favorable biocompatibility, inherent targeting ability, and unique immunoregulatory capacity to NPs, thereby enhancing tumor immunotherapy. However, this integration simultaneously complicates the interaction mechanism between NPs and the biological environment, thereby exhibiting potential inflammatory risks (Zinger, 2023). In order to address this issue, high-throughput screening methods can be employed to identify biomimetic NPs with optimal characteristics during the research process. The characterization of biomimetic NPs is hindered by their complex structures and compositions, necessitating the establishment of simplified models for separate analysis of performance attributed to specific natural components. Moreover, the synthetic method for biomimetic NPs relies on large-scale cell culture and purification of specific biological components followed by strict storage conditions requirements that impede their clinical translation. Therefore, it is imperative to establish stringent production standards and evaluation criteria to ensure the uniformity of source cells and extracted biological components, as well as the stability in the performance of final biomimetic NP products.

Hybrid NPs

Hybrid NPs, also referred to as multi-component NPs, are defined as nanoscale composites composed of at least two constituents with distinct compositions and properties. They possess the unique capability to integrate the advantages of different materials and overcome the inherent limitations of single materials, while also demonstrating potential for novel properties resulting from hybridization (Rajana et al., 2022; Li et al., 2023c). This section provides a summary of representative categories of hybrid NPs, including metal-organic frameworks (MOFs), mesoporous organosilica nanoparticles (MONs), metallofullerene NPs, and lipid–polymer hybrid NPs (LPHNs).

MOFs

MOFs are crystalline structures with a three-dimensional arrangement, characterized by an organized framework resulting from the self-assembly of metal ions or clusters and organic struts connected by coordination bonds (Luo et al., 2019b). The versatility in coordinating metal ions and organic struts facilitates the synthesis of personalized MOFs tailored to various pharmaceuticals with diverse molecular weights, hydrophilic properties, and sizes (Gao et al., 2021). The significant surface areas, exceptional porosities, and weak coordination bonds of MOFs contribute to their high loading capacity and biodegradability, making them promising candidates for drug delivery systems (Wu and Yang, 2017). The incorporation of specific active metal ions and functional linkers into framework structures can endow the MOFs with diverse functionalities, including stimuli-responsiveness, imaging and biosensing properties, synergistic antitumor effect, and even direct antitumor activity (Gao et al., 2021). For instance, an ultrathin ferrocene-based MOF can function as a photothermal agent and Fenton catalyst to mediate simultaneous photothermal therapy and chemodynamic therapy (CDT) without requiring additional drugs (Deng et al., 2020).

MONs

MONs are engineered to address concerns regarding the potential toxicity associated with the prolonged retention of traditional MSNs, achieved by integrating organic moieties into the Si–O–Si frameworks in a covalent manner to promote degradation under physiological conditions (Cheng et al., 2020). MONs offer numerous advantages including improved biodegradability, biocompatibility, uniform morphology, and large surface areas (Chen and Shi, 2016). Furthermore, the diverse functionalization of organic moieties endows MONs with favorable attributes for controlled release, targeted delivery, and specific interaction with guest molecules through electrostatic forces, chemical bonding, or noncovalent interactions (Yang et al., 2019).

Metallofullerene NPs

Metallofullerene NPs are permanent ionic compounds synthesized by encapsulating metal atoms or metal clusters within a closed fullerene cage, which remain intact until the carbon cage is destroyed (Grebowski and Litwinienko, 2022). In addition to their stability, they offer the advantages of easy functionalization and antitumor activity (Wang and Wang, 2019). Metallofullerene NPs also demonstrate diverse chemical, optical, and magnetic properties due to variations in fullerene cages and metal components (Li et al., 2021). Gd@C₈₂(OH)₂₂ NPs are representative metallofullerene antitumor nanomedicines with biosafety, biocompatibility, and well dispersibility in physiological solutions, which inhibit tumor growth and metastasis via multiple mechanisms (Li et al., 2012, 2019).

LPHNs

LPHNs refer to NPs composed of an internal polymeric core and an outer lipid shell, which may consist of one or multiple layers (Gowsalya et al., 2021). The design of lipid layers aims to enhance the stability of NPs, prevent aggregation, and prolong circulation time following surface engineering, while the polymer core ensures structural integrity to support the lipid layers as well as achieve stimuli-responsive release of diverse cargos (Khalili et al., 2022; Tang et al., 2022). LPHNs possessing high stability, excellent biocompatibility, and low toxicity have the capability to encapsulate a variety of therapeutic agents, regulate cargo release, and achieve synergistic delivery of multiple therapeutic agents (Bose et al., 2017). LPHNs have been validated as an effective delivery system for CRISPR/Cas9 plasmids, ultimately restoring the sensitivity of glioblastoma cells through gene editing facilitated by focused ultrasound and microbubbles (Yang et al., 2021b).

Numerous studies have utilized synergistic combinations of multiple nanomaterials to enhance the performance of nanomedicines and expand the application scope of nanomedicines. However, due to the complex properties exhibited by these hybrid systems, further long-term characterization is necessary to assess their stability, toxicity, drug distribution, metabolism, and immune response in vivo (Dormont et al., 2019; Stater et al., 2021). Additionally, the increasing complexity of nanomedicine design encompassing multiple raw materials and intricate preparation processes complicates scaling up manufacturing as well as subsequent sterilization and storage conditions. Therefore, it is imperative to consider manufacturing constraints for scale-up production of nanomedicines during the initial design phase.

Nanomedicine in tumor immunotherapy

Tumor immunotherapy holds great promise in harnessing the immune system to eliminate tumors, prevent metastasis, and reduce recurrence (Liu et al., 2022d). It encompasses seven main categories, including ICBs, mAb therapy, cytokine therapy, tumor vaccine, ACT, OV immunotherapy, and immune combination therapy (Figure 3). Nevertheless, there remains a pressing need to optimize the delivery efficiency, toxicity profiles, and response rates of tumor immunotherapy agents. Nanomedicine in the form of nanoformulation has the potential to target specific sites, minimize off-target accumulation, control cargo release, and coordinate multiple therapies (Alqosaibi, 2022). Therefore, the application of nanomedicine in tumor immunotherapy aims to address these challenges and maximize efficacy. In the following sections of this review, we will introduce the application of nanomedicines in various modalities of tumor immunotherapy (Table 1).

Figure 3.

Schematic diagram of the principles of cancer immunotherapy. The fundamental principle of tumor immunotherapy is to stimulate the immune system of patients to recognize and eliminate tumor cells, while also establishing long-term memory. Specifically, ICBs are designed to introduce inhibitors that disrupt the interaction between inhibitory checkpoint molecules and their corresponding ligands, thereby enabling immune cells to function effectively. mAb therapy aims to block signal pathways involved in tumorigenesis or activate the immune response to inhibit tumor growth. Cytokine therapy is intended to supplement various cytokines in order to stimulate multiple immune cells and signal pathways. Tumor vaccines are designed to provide effective tumor antigens for activating antigen-specific responses, ultimately leading to the elimination of tumor cells. ACT, exemplified by CAR-T therapy, aims to harness the potential of natural or genetically modified lymphocytes for the eradication of tumor cells. CAR-T cells are engineered with CAR genes to enhance their capacity in identifying and eliminating cells expressing specific antigens. OV therapy is designed to exploit OVs for the invasion and lysis of tumor cells. Immune combination therapy is intended to integrate immunotherapy with other modalities capable of inducing ICD, thereby remodelling the TME and augmenting the immune response. This figure is created with BioRender.com.

Table 1.

A list of representative NPs applied in immunotherapy across various cancer types.

Tumor immunotherapy type	Advantage	Major cargo	NP	Cancer type	References
ICBs	Directly target inhibitory checkpoint molecules and mitigate off-target accumulation	Antibody	• Mesoporous silica NPs • Polymeric NPs • DC-derived nanovesicles	• Melanoma • Prostate cancer	Zhao et al. (2021); Jung et al. (2022); Wang et al. (2023a)
		Small-molecule inhibitor	• Dendrimer-entrapped gold NPs • Lipid–calcium–phosphate NPs • Lipid-based NPs	• Melanoma • Glioblastoma multiforme • Lung cancer	Wan et al. (2021); Xue et al. (2021); Hsieh et al. (2022)
	Mediate gene therapy to modulate the expression of multiple checkpoint molecules	siRNA	• ZIF-8 NPs • Polymer-based NPs	• Osteosarcoma • Colorectal cancer	Yu et al. (2021); Ge et al. (2022)
		miRNA	• Cationic polymer-based NPs	• Colon carcinoma	Nguyen et al. (2021)
		mRNA	• Lipid-based NPs	• Melanoma	Walters et al. (2021)
mAb therapy	Enhance tumor-specific accumulation, minimize off-target toxicity, and optimize therapeutic efficacy	Bevacizumab	• Polymer-coated human serum albumin NPs	• Colorectal cancer	Luis de Redin et al. (2020)
		Trastuzumab	• Human ferritin NPs	• Breast cancer	Sevieri et al. (2023)
		Cetuximab	• Silica NPs • Lipid-coated mesoporous silica NPs	• Hepatocellular carcinoma • Colon carcinoma	Wang et al. (2017); Chen et al. (2021b)
Cytokine therapy	Preserve cytokine activity, enhance targeted accumulation, and minimize systemic exposure	Interleukin	• Polymer-based NPs	• Ovarian cancer • Colorectal cancer	Barberio et al. (2020)
	Achieve consistent and elevated levels of cytokine expression	mRNA	• Polymer-modified porous silica NPs • Lipid NPs • Cationic liposomes	• Melanoma • Colon carcinoma	Lei et al. (2020); Liu et al. (2022b); Shin et al. (2023)
		Self-replicating RNA	• Lipid NPs	• Melanoma	Li et al. (2020)
Tumor vaccine	Facilitate antigen protection, enable efficient delivery, prolong antigen presentation by APCs, and enhance T-cell immune infiltration	Protein/peptide antigen	• Lipid NPs • Polymer-based NPs • Mesoporous silica microrods • Graphene oxide NPs • MnO2 NPs • Ultra-small Fe3O4 NPs • Virus-like gold NPs	• Melanoma • Colorectal cancer • Colon carcinoma • Lymphoma	Luo et al. (2019a); Nguyen et al. (2020b); Xu et al. (2022); Zhang et al. (2022a); Gu et al. (2023); Liu et al. (2023b); Su et al. (2022, 2023); Zhao et al. (2022a); Li et al. (2023d); Wang et al. (2023b)
		mRNA antigen	• Lipid NPs • Ionizable polymeric NPs	• Melanoma • Glioblastoma multiforme	Chen et al. (2022)
	Provide abundant antigen epitopes and activate robust immune responses	Natural signal molecules from cells	• Fusion cell membrane-coated NPs • Polymer-based NPs • Tumor cell membrane-coated chitosan-shell PLAG-core NPs • DC-derived exosomes • Tumor cell-derived exosome-like nanovesicles	• Hepatocellular carcinoma • Colon carcinoma • Melanoma • Lung carcinoma • Breast cancer	Hu et al. (2021); Zhang et al. (2022b); Zuo et al. (2022); Liu et al. (2023a)
ACT	Promote antigen-specific T-cell proliferation ex vivo	TCR activation and co-stimulation signals	• Iron–dextran NPs • Polymer-based NPs	/	Song et al. (2019); Ichikawa et al. (2020).
	Program T cells directly in situ, eliminating the need for isolating T cells from their physiological environment and reinfusion of CAR-T cells	mRNA	• Polymeric NPs	• Lymphoma • Prostate cancer • Hepatocellular carcinoma	Parayath et al. (2020)
		Plasmid	• Lipid NPs	• Leukemia	Zhou et al. (2022)
	Modulate the immunosuppressive TME to enhance CAR-T cell homing and expansion and sustain their functional persistence	Immunoregulatory agent	• Lipid NPs • Protein nanogels • Multilamellar liposomal vesicles	• Breast cancer • Melanoma • Ovarian carcinoma	Siriwon et al. (2018); Tang et al. (2018); Zhang et al. (2018)
OV therapy	Escape from neutralizing antibodies and extend the duration of viral circulation	OV	• Cationic gold NPs	• Prostate cancer	Man et al. (2022)
	Enable the in situ generation of oncolytic virus and facilitate repeated intravenous administration	Viral RNA genome	• Lipid NPs	• Small cell lung cancer	Kennedy et al. (2022)
	Demonstrate inherent selective oncolysis capabilities	No additional cargo	• Repebody-apoptin self-assembled protein NPs	• Breast cancer	Lee et al. (2017)
			• Polymer-based NPs	• Pancreatic cancer • Melanoma • Liver cancer	Liu et al. (2022c); Yu et al. (2023)
Immune combination therapy	Elicit ICD, remodel the TME, and optimize the effectiveness of combination or sequence treatments	Photothermal agent or photothermal nanomaterial	• Mesoporous silica NPs • Intracellularly generated immunological gold NPs • Ultrasmall FeS-GOx nanodots	• Melanoma • Breast cancer	Huang et al. (2021a); Zhang et al. (2019a); Ren et al. (2021)
		Photosensitizer	• Large-pore mesoporous silica shell • Hyaluronic acid nanomicelles • Polydopamine NPs	• Metastatic spine tumor • Breast cancer • Colon carcinoma	Le et al. (2019); Wang et al. (2021c); Wu et al. (2021)
		Chemotherapeutic agent	• Self-assembled polymer micelles • Hollow aluminum hydroxide-modified silica NPs • Metal–phenolic hybrid NPs	• Breast cancer	Tan et al. (2022); Cheng et al. (2023); Zhang et al. (2023c)
		Radiosensitizing nanomaterial	• Vesicle membrane-coated gold NPs • Lipid-modified manganese diselenide NPs • Hollow MnO2 NPs	• Colorectal tumor • Esophageal squamous cell carcinoma	Qin et al. (2021b); Guan et al. (2022); Li et al. (2024a)

Nanomedicines in ICBs

ICBs were initially developed to disrupt the interaction between inhibitory checkpoint molecules and their corresponding ligands, which have an immunosuppressive effect, thereby enabling immune cells to become activated. Representative inhibitory checkpoints include PD-1, programmed cell death-ligand 1 (PD-L1), indoleamine 2,3-dioxygenase (IDO), and cytotoxic T lymphocyte (CTL)-associated antigen-4 (CTLA-4). Furthermore, an increasing number of stimulatory checkpoint molecules have been harnessed to enhance the immune response through the use of agonistic antibodies in ICB therapy (Marhelava et al., 2019).

Considering the pivotal role of checkpoints in maintaining immune system homeostasis, the unintended off-target accumulation of immune checkpoint inhibitors may trigger immune-related adverse events implicating multiple organs and potentially leading to tumor hyperprogression (Kamada et al., 2019; Okiyama and Tanaka, 2022). Nanomedicine represents a promising approach in the field of immune checkpoint inhibitor delivery, with a diverse array of nanomedicines such as lipid NPs, polymer NPs, biomimetic NPs, MSNs, LPHNs, and others being utilized to modulate checkpoint molecules, demonstrating the capacity to enhance targeting precision and mitigate off-target toxicity (Luo et al., 2018; Zhao et al., 2021; Yu et al., 2022b; Tan et al., 2023). For instance, Wang et al. (2023a) have developed a pH-responsive polymeric nanomedicine that incorporates anti-PD-L1 antibodies and a long-chain PEG coating. The inclusion of the PEG coating serves to mitigate nonspecific cellular uptake and off-tumor accumulation, subsequently facilitating the release of the anti-PD-L1 antibody in response to the acidic TME. In a study conducted by Jung et al. (2022), DC-derived nanovesicles loaded with tumor antigens were employed for the delivery of anti-CTLA-4 antibodies, demonstrating enhanced specific targeting capability towards tumor-specific T cells. As a result, these nanomedicines exhibited enhanced antitumor efficacy without eliciting immune-related adverse events.

Gene therapy provides an alternative approach to traditional antibody-based ICBs, with the potential to either eliminate inhibitory checkpoints or enhance stimulatory checkpoint levels through the introduction of multiple RNAs, thereby contributing to the eradication of cancer. Nanomedicines are increasingly assuming a pivotal role in integrating gene therapy with ICBs (Kiaie et al., 2023). It has been revealed that, in comparison to antibody-based blockades, immune checkpoint silencing based on siRNA-loaded nanomedicines has demonstrated superior efficacy in tumor inhibition (Xue et al., 2021; Won et al., 2022). The observed phenomenon can be attributed to the fundamental suppression of the expression and secretion of checkpoint molecules by siRNA. Moreover, lipid–calcium–phosphate-based NPs have been employed to improve the efficacy of PD-L1 siRNA delivery through the blood–brain barrier (BBB), resulting in the inhibition of glioblastoma multiforme growth (Hsieh et al., 2022). Nanomedicines allow for the simultaneous delivery of multiple RNA molecules to achieve a synergistic effect. An illustrative example is the ROS-responsive polymer nanomedicines co-loaded with siRNAs targeting fibrinogen-like protein 1 (FGL1) and PD-L1, enabling concurrent inhibition of the PD-1/PD-L1 and FGL1/LAG-3 signaling pathways (Wan et al., 2021). It is evident that such dual-pathway blockades have significantly improved the immunosuppressive TME, surpassing single blockade approaches. Lipid nanomedicines co-delivering siRNA and mRNA effectively downregulated PD-L1 expression while concurrently upregulating OX40L levels, resulting in potent inhibition of tumor growth and enhanced immune infiltration with minimal toxicity (Walters et al., 2021).

Another challenge associated with ICBs is the evasion of patients’ immune systems, leading to a low response rate and limited clinical effects. This can be partly attributed to the downregulation of tumor immunogenicity and insufficient infiltration of T lymphocytes (Kim et al., 2018). Therefore, nanomedicines have been developed to harmonize ICBs and multiple immune regulatory reagents to modulate TME as well as alleviate tolerance to ICBs (Wang et al., 2018; Feng et al., 2022). For example, Ge et al. (2022) developed a co-delivery system using modified zeolitic imidazolate framework-8 (ZIF-8) MOFs to encapsulate curcumin (an autophagy activator) and BMS1166 for ICB. This was based on the rationale that autophagy enhances antigen presentation, promotes CTL sensitivity, and induces immunogenic cell death (ICD) (Ge et al., 2022). The results demonstrated that the co-delivery system effectively suppressed tumor growth and elicited strong and durable immune memory against tumor recurrence by distinctly inducing DC maturation and potent ICD. Additionally, polymer nanomedicines were designed to load plasmid DNA encoding immunostimulatory chemokine CCL19 and PD-L1 inhibitor (BMS-1), aiming to stimulate multiple immune regulatory pathways (Yu et al., 2021). Following the administration of these nanomedicines, a significant improvement in TME was observed, characterized by high local concentrations of immunostimulatory cytokines and synergistically enhanced antitumor efficacy. The combination of targeted therapy using BRAF inhibitor and PD-L1 inhibition through miR-200c, delivered via polymer nanomedicines conjugated with CXCR-4 antagonist peptides, resulted in a potent immune response with increased T-lymphocyte infiltration and decreased number of Treg cells (Nguyen et al., 2021).

Overall, the integration of nanomedicines with ICBs holds great promise for mitigating associated adverse effects and improving treatment outcomes by enabling targeted delivery, incorporating gene therapy, and coordinating multiple immunoregulatory agents.

Nanomedicines in mAb therapy

mAbs refer to a class of antibodies that specifically recognize and bind to a particular antigen epitope, and have been extensively investigated in the field of tumor immunotherapy. Structurally, mAbs consist of Fv and Fc regions, which respectively govern the affinity of mAbs and their ability to interact with the immune system (Kimiz-Gebologlu et al., 2018). Taking advantage of their specificity and versatility, mAbs can be engineered to achieve antitumor efficacy through various mechanisms, broadly categorized as either blocking signal pathways involved in tumorigenesis or activating the immune response to inhibit tumor growth (Carvalho et al., 2016). However, mAb therapy is confronted with challenges such as high background expression of the corresponding antigen, undesirable side effects, and development of resistance mechanisms as well as low tumor penetration (Christiansen and Rajasekaran, 2004).

Nanomedicines provide a practical and straightforward approach to enhance mAb therapy. The conjugation of cetuximab with gold NPs improved the inhibition of epidermal growth factor receptor (EGFR) signaling and significantly reduced the receptor recycling process, resulting in enhanced therapeutic effects at lower cetuximab dosages (García-Fernández et al., 2017). A study conducted by Luis de Redín et al. (2020) revealed that bevacizumab-loaded albumin nanomedicines effectively increased intratumor levels of bevacizumab while reducing accumulation in the bloodstream compared to the free formulation, indicating a decreased risk of side effects and improved antitumor efficacy. A study by Truffi et al. (2018) demonstrated that the diversified arrangement of trastuzumab half chains on the surface of magnetic iron oxide NPs contributed to an enhanced antitumor effect and mitigated trastuzumab-resistance in HER2⁺ breast cancer cells, while also exhibiting favorable targeting properties. Taking into account the ability of ferritin to permeate the trans-BBB via TfR1, Sevieri et al. (2023) synthesized trastuzumab-conjugated ferritin nanomedicines for the treatment of brain metastasis of HER2⁺ breast cancer. Consequently, these nanomedicines exhibited efficient accumulation in the brain, reduced off-target toxicity, and improved efficacy upon systemic administration. Moreover, mAbs-modified nanomedicines are employed to achieve binary drug delivery in conjunction with additional therapeutic agents, capitalizing on their precise targeting and efficient accumulation in tumors (Wang et al., 2017). An example in point is the development of cetuximab-modified MSN-based nanomedicines by Chen et al.  (2021b). These nanomedicines maintained the capability to suppress the EGFR-associated signaling pathway while enhancing the antitumor efficacy of encapsulated chemotherapeutics.

Nanomedicines in cytokine therapy

Cytokines, small soluble proteins secreted by a variety of cells, mediate multiple signaling pathways and directly participate in regulating the immune system. They also play a crucial role in tumor pathogenesis and antitumor immune response. Therefore, cytokines such as interleukin-2 (IL-2), type I interferon (IFN), IL-12, and chemokine (C–C motif) ligand 21 (CCL21) have been employed for antitumor immunotherapy (Qiu et al., 2021). However, frequent and high-dose administration is required for cytokine delivery owing to their short half-life (Dholakia et al., 2022). Additionally, the administration of cytokines often leads to systemic toxicity due to their nonspecific internalization by a wide range of cells with appropriate receptors. In response to these challenges, nanomedicines loaded with cytokines have been developed for cytokine therapy, capitalizing on their ability to achieve sustained drug concentrations and adequate tissue deposition without reaching toxic loading doses associated with systemic administration (Ye et al., 2014; Lacinski et al., 2022). As an example, a liposome conjugated with IL-2 was modified with polyelectrolyte layer-by-layer to construct a nanomedicine (Barberio et al., 2020). The polymer layers served as camouflage to maintain cytokine activity, reduce systemic exposure, and selectively localize on the tumor membrane. This approach resulted in favorable efficacy and reduced toxicity at equivalent doses in multiple cancer models.

The employment of nanomedicines for the transfection of nucleic acid-encoding cytokines offers a preferable alternative to cytokine delivery, due to its advantages in efficient delivery, internalization, and localized and sustained production (Nguyen et al., 2020a). The intratumoral administration of artificially engineered IL-2 encoding mRNA via polyethyleneimine-modified porous silica NPs gave rise to high-level expression of the protein, remodelling of TME, and enhanced antitumor efficacy (Shin et al., 2023). Based on the screening results from a library of diverse ionizable lipids, Xu et al. (2024) synthesized innovative lipid NPs with intrinsic stimulation capability of the nuclear factor-κB (NF-κB)/IRF immune pathway. These NPs significantly enhanced transfection efficiency for IL-12 circular RNA and promoted immune infiltration, leading to tumor regression following a singular intratumoral administration (Xu et al., 2024). Lipid-based NPs encapsulating both IL-12 mRNA and IL-27 mRNA exhibited a significant synergistic effect, leading to the robust infiltration of immune effector cells without inducing systemic toxicity (Liu et al., 2022b). Ionizable lipid nanomedicines containing self-replicating IL-12 RNAs facilitated high-level expression of IL-12, while also eliciting a highly inflamed TME through the intrinsic cytotoxicity of the carriers (Li et al., 2020).

Nanomedicines in the tumor vaccine

The tumor vaccine is a formulation incorporating tumor antigens and adjuvants, aimed at stimulating the antigen-specific response of patients’ immune systems to eliminate tumor cells and establish long-term immunological memory (Gurunathan et al., 2024). The integration of nanomedicines into tumor vaccines as delivery systems enhances the overall vaccine efficacy, providing improved characteristics such as antigen protection, precise targeting, controlled release, prolonged antigen presentation by antigen presenting cells (APC), and enhanced T-cell immune infiltration (Mueller et al., 2015; An et al., 2017; Smith et al., 2022; Zhao et al., 2023). Besides, the nanomedicines possess the capability to optimize vaccine immune phenotype by tailoring physicochemical properties (Qin et al., 2021a). Vaccines formulated at the nanoscale are commonly known as nanovaccines. Various types of nanomaterials have been utilized for the development of tumor nanovaccines, which can be broadly categorized into lipid-based, polymer-based, inorganic-based, and biomimetic tumor nanovaccines based on their respective material compositions.

In the field of nanovaccines, lipid nanomedicines have garnered significant attention, particularly in light of the success achieved with lipid-based COVID-19 mRNA vaccines. The utilization of lipid nanomedicines has been extensive in the development of tumor vaccines and has also been translated into commercially viable products due to their scalable manufacturing processes (Aldosari et al., 2021). Owing to the facile adjustment of lipid composition, a diverse array of lipid-based nanovaccines has been developed. For instance, through screening a library of lipid formulations, lipids with an unsaturated lipid tail, a dihydroimidazole linker, and cyclic amine head groups were identified as optimal candidates for mRNA nanovaccines due to their ability to activate the stimulator of interferon genes (STING) pathway and induce APC maturation, thereby enhancing antitumor efficacy (Miao et al., 2019). Heterocyclic lipid nanomedicines have been utilized for targeted delivery to draining lymph nodes and activation of STING. These nanomedicines were employed to encapsulate ovalbumin (OVA) antigen and signal transducer and activator of transcription 3 (STAT3) siRNA, resulting in a favorable anticancer response (Liu et al., 2023b). Li et al. (2023d) developed minimal-component nanovaccines derived from monophosphoryl lipid A, which is a Toll-like receptor-4 immune agonist. Consequently, these nanovaccines induced a shift in TME to an immunologically ‘hot’ state and successfully increased the ratio of CD8⁺ T cells/Tregs. Chen et al. (2022) constructed spontaneous lymph node-targeting lipid mRNA nanovaccines without ligand modification as a versatile platform enabling easy production. Consequently, these nanovaccines mitigated undesirable hepatic mRNA expression following subcutaneous administration and elicited enhanced APC infiltration at the tumor sites.

Polymer nanomedicines, characterized by their structural diversity, biocompatibility, biodegradability, and modifiability, have been widely embraced as vaccine platforms. For instance, Xu et al. (2022) designed a mannan-modified polymeric nanovaccine with protein antigens and CpG coupling to the polymeric core via electrostatic interactions. These nanovaccines evoked favorable antitumor effects in several murine tumor models with significantly increased accumulation in CD8⁺ DCs. Additionally, Zhao et al. (2022a) synthesized simplified polymeric nanovaccines incorporating innate stimulating properties based on polyethyleneimine with azole molecules at the end. These nanovaccines have demonstrated superior performance compared to the traditional ternary vaccine system, offering the advantage of meeting individual requirements through combination with autologous tumor membrane protein antigens. Furthermore, stimuli-responsive polymer nanovaccines exhibit promising potential by enabling intelligent delivery for achieving spatiotemporally controlled release, preventing content inactivation, and enhancing specific uptake of APCs as well as the cytosolic release (Zhou et al., 2020; De Mel et al., 2022; Mao et al., 2023). Su et al. (2023) developed a pH-responsive polymeric nanovaccine from multiple functional blocks, which separately facilitated electrostatic and hydrophobic interactions as well as maintained pharmaceutical stability. As a result, these nanovaccines demonstrated the capability to coordinate bi-adjuvant and peptide neoantigens, leading to the alleviation of tumor immunosuppression and enhanced antitumor responses. A pH-responsive nanovaccine was synthesized leveraging self-assembled polymers, allowing for the simultaneous loading of novel cyclic dinucleotide adjuvants and neoantigens (Su et al., 2022). These nanovaccines facilitated endosomal escape and content release in response to acidic conditions, subsequently eliciting robust antigen-specific T-cell responses with immune memory.

Inorganic nanomedicines with well-defined physicochemical properties, high surface-to-volume ratio, uniformity, and facile preparation are advantageous for the design of nanovaccines (Hess et al., 2019). For instance, a nanovaccine derived from mannose-modified multi-walled CNT exhibited low cytotoxicity, impressive antigen-loading capacity, and specific DC targeting, turning out to evoke an effective immune response (Dong et al., 2019). An antigen-coding DNA-loaded nanovaccine was developed based on mesoporous silica microrods, which have the ability to self-assemble into 3D scaffolds at the injection site (Nguyen et al., 2020b). The macroporous structure of the scaffold facilitated the recruitment and sustained DNA uptake of host DCs, leading to the generation of Th1 humoral responses and CD8⁺ T-cell responses. In a study conducted by Wang et al. (2023b), Au nanovaccines loading OVA were constructed with virus-like spiky surfaces. These nanovaccines demonstrated efficient delivery and cross-presentation of antigens, along with good biocompatibility and potent adjuvant activity due to their biomimetic structures. The graphene oxide-based nanovaccines synthesized by Zhang et al. (2022a) presented a significant impact on tumor suppression, as they were capable of promoting DC maturation and secretion of proinflammatory cytokines. Several metal nanomedicines, when used as delivery systems, have the capability to directly regulate the immune response through various mechanisms, rendering it feasible to coordinate with nanovaccines (Li et al., 2022a; Yavuz et al., 2023). An illustrative example is the MnO₂ nanovaccines loading OVA constructed by Gu et al. (2023), which functioned as a source of Mn²⁺ to stimulate the STING pathway. As a result, the immunosuppressive TME was reprogrammed through macrophage repolarization and DC maturation. Furthermore, Fe₃O₄ nanocarriers were identified to be involved in macrophage activation and DC maturation, leading to the inhibition and prevention of subcutaneous or metastatic tumor growth when combined with OVA (Luo et al., 2019a).

Biomimetic nanomedicines have expanded the scope of nanotechnology in the development of nanovaccines, which have been verified to contribute to enhanced biosafety and better antitumor responses (Yang et al., 2020; Johnson et al., 2022). Membrane coated nanovaccines preserve the biological functionality of their source cells and enable the loading of antigens and other therapeutic agents within synthetic cores (Liu et al., 2022a). For instance, the fusion membranes resulting from DCs and tumor cells retained tumor cell membrane antigens as well as MHC and co-stimulatory molecules from mature DCs. As a result, the fusion membrane coating equips NPs with the ability to directly and indirectly initiate specific immune responses (Zhang et al., 2022b). In a study conducted by Liu et al. (2023a), a novel nanovaccine encapsulating tumor-specific antigen (TSA) was camouflaged with cell membranes derived from tumors going through ICD. Leveraging the simultaneous delivery of TSA and a wide range of membrane-associated antigens, this nanovaccine demonstrated the ability to overcome tumor immune suppression and evasion. Exosomes have been extensively employed in the development of tumor nanovaccines, demonstrating superior efficacy compared to liposomal formulations due to the presence of exosomal proteins (Li et al., 2023b). In a study led by Zuo et al. (2022), a personalized nanovaccine with universal applicability was developed using DC-derived exosomes. These exosomes were modified to display an α-fetoprotein epitope, a functional domain of high mobility group nucleosome-binding protein 1, and a hepatocellular carcinoma-targeting peptide. This design enabled the nanovaccine to serve dual functions, (i) as DC vaccines and (ii) to recruit and activate endogenous DCs at tumor sites, thereby eliciting tumor-specific immune responses against neoantigens. Hu et al. (2021) isolated exosomes from tumor cells engineered with the fibroblast activation protein-α gene to develop nanovaccines. It is noteworthy that these exosome-based nanovaccines effectively target both the tumor parenchyma and stroma, thereby mitigating immunosuppression and inhibiting tumor growth in an innovative manner.

In conclusion, a wide range of nanomedicines have been utilized in the development of tumor vaccines, showcasing significant potential in addressing the challenges encountered by traditional vaccine formulations, such as relatively low immunogenicity, limited delivery efficiency, and immunosuppressive TME. The diverse physicochemical properties of nanomaterials and their adaptable modifications contribute to the precise design of nanovaccines tailored for specific antigen-adjuvant combinations, action sites, and types of tumors. This ultimately leads to enhanced immune responses and improved therapeutic efficacy.

Nanomedicines in ACT

ACT is designed to utilize the potential of natural or genetically modified lymphocytes for the identification and eradication of tumors, typically involving original cell extraction, in vitro manipulation, and subsequent back-infusion (Rosenberg et al., 2023). Tumor-infiltrating lymphocytes, engineered T-cell receptor (TCR)-T cells, and chimeric antigen receptor (CAR)-T cells are representative categories of ACT (June et al., 2018). Among them, CAR-T therapy has made remarkable clinical advancements with six products approved by the FDA so far. CAR-T cell therapy entails the modification of T cells to express CARs, enabling them to precisely identify and eliminate cells expressing a specific antigen (Sterner and Sterner, 2021). The current synthesis process of CAR-T cells primarily relies on in vitro gene editing of extracted T cells, which is both costly and intricate (Billingsley et al., 2020). In addition to the complicated in vitro synthesis procedures, the application of CAR-T cell therapy subjects to insufficient T-cell expansion and a short valid period as well (Zheng et al., 2021). To address these issues, the utilization of nanomedicines has been introduced to expedite T-cell expansion, mediate in situ T-cell transfection, and maintain the functional persistence of back-infused CAR-T cells.

The adequate quantity of T cells is a prerequisite for achieving optimal ACT efficacy. Nanomedicines designed to imitate natural APCs by conveying immunostimulatory signals have been broadly employed to promote the activation and proliferation of isolated T cells (Zheng et al., 2021; Figure 4A). These nanomedicines are termed nanoscale artificial APC (nano-aAPC), characterized by providing two signals including TCR activation and co-stimulation (Wang et al., 2021b). As an example, iron–dextran nano-aAPCs carrying anti-CD28 and human MHC-I molecules binding antigenic peptides have possessed the ability to rapidly promote antigen-specific T-cell proliferation up to 1000-fold in vitro (Ichikawa et al., 2020). Additionally, paramagnetic iron–dextran nano-aAPCs have been identified to contribute to the aggregation of TCR clusters in an externally applied magnetic field, thereby further facilitating T-cell activation and proliferation both in vitro and in vivo (Perica et al., 2014). Song et al. (2019) developed a PEGylated PLGA ellipsoidal nano-aAPC coupled with H-2Kb/TRP2180-188-Ig dimers, anti-CD28, and CD47-Fc, achieving enhanced antigen-specific T-cell proliferation while minimizing cellular uptake.

Figure 4.

Schematic diagram of the mechanism of nanomedicines in CAR-T therapy. (A) Through the incorporation of TCR activation signals such as pMHC and co-stimulation signals such as anti-CD28 antibody, nanomedicines are engineered to mimic APCs in order to enhance ex vivo T-cell activation and proliferation. This strategy is referred to as nanoscale artificial APC. (B) The application of DNA/mRNA-bearing nanomedicines enables the direct programming of T cells in situ upon administration, thereby eliminating the need for isolating T cells from their physiological surroundings. (C) Nanomedicines loaded with immunomodulatory reagents, which are coupled to the surface of CAR-T cells, have the ability to infiltrate tumor sites, effectively reshaping the immune microenvironment while simultaneously preserving the viability of CAR-T cells. This figure is created with BioRender.com.

Nanomedicines have the potential to serve as substitutes for conventional transfection methods, such as viral vectors and electroporation. They demonstrate low immunogenicity, improved transfection efficiency, enhanced safety, and reduced cytotoxicity (Zeng et al., 2023). Furthermore, DNA/mRNA-bearing nanomedicines that are modified with targeting ligands provide a straightforward and cost-effective approach to directly program T cells in situ (Figure 4B). This eliminates the necessity of isolating T cells from their physiological environment (Parayath and Stephan, 2021). Importantly, the in situ programming method based on nanomedicines enables precise targeting, reduced nonspecific internalization, and mitigated side effects associated with CAR-T therapy (Sledz et al., 2023). As an example, Parayath et al. (2020) developed injectable polymeric nanomedicines modified with anti-CD8 antibodies for the delivery of CAR-coding mRNA, enabling efficient large-scale manufacture and long-term storage, thus facilitating convenient repeated administration. These nanomedicines transiently reprogramed circulating T cells to activate antitumor responses with transfected T cells expressing CAR for an average of 7 days. Furthermore, lipid nanomedicines modified with the anti-CD3 antibody were employed to encapsulate plasmids containing IL-6 short hairpin RNA (shRNA) and the CD19-CAR gene (Zhou et al., 2022). The resulting IL-6-knockdown CAR-T cells exhibited reduced IL-6 release following transfection, thereby mitigating the risk of cytokine release syndrome while demonstrating antitumor effects comparable to in vitro-prepared CAR-T cells.

The presence of cytokines and inhibitory molecules from tumor-associated immunosuppressive cells and the tumor itself can lead to rapid loss of validity of CAR-T cells (Kong et al., 2023). Therefore, the administration of CAR-T cells necessitates concurrent delivery of carefully selected adjuvants to modulate the immunosuppressive TME and sustain the functional persistence of CAR-T cells. Nanomedicines provide a targeting platform for supporting CAR-T cells while minimizing systemic exposure of adjuvants. The internalizing RGD peptide (iRGD)-modified lipid nanomedicines carrying a combination of phosphatidylinositol 3-kinase (PI3K)-δ inhibitors and α-GalCer agonists have been demonstrated to induce a transition in the TME from suppressive to stimulatory (Zhang et al., 2018). This resulted in the establishment of a therapeutic window lasting 2 weeks following repeated administration, thereby facilitating subsequent CAR-T cell homing, expansion, and successful tumor regression. In addition, surface conjugation with nanomedicines has been demonstrated to synchronize the efficacy of back-infused CAR-T cells and adjuvant treatments preferably, ultimately preserving CAR-T cell activity and enhancing therapeutic efficacy (Stephan et al., 2010; Figure 4C). For example, protein nanogels have been utilized to load the IL-15 superagonist complex and then conjugated in large quantities to the T-cell surface. This backpack strategy allows for higher dosages of cytokine administration tolerance compared to systemic delivery of free cytokines, leading to significant amplification of T cells and ultimately improving CAR-T cell therapy (Tang et al., 2018). Furthermore, coupling nanomedicine with CAR-T cells results in prolonged circulation and reduced liver clearance, taking advantage of the inherent mobility of T cells to penetrate deep inside tumors. This contributes to better performance in restoring the activity of hypofunctional CAR-T cells (Siriwon et al., 2018).

In summary, nanomedicines not only optimize the in vitro manufacturing strategy of CAR-T cells but also offer a versatile platform for in vivo programming and functional maintenance of CAR-T cell-mediated antitumor effects, thereby expanding their potential clinical applications with cost-effectiveness, convenient operation, and personalized design.

Nanomedicines in OV immunotherapy

OVs, comprising protein shells and nucleic acids, present high invasiveness, robust replication, and rapid propagation capabilities within tumor cells. They possess the capability to lyse tumor cells and subsequently trigger an immune response (Fang et al., 2023a). Systemic delivery of OVs is the preferred clinical method owing to its simplicity and extensive coverage of tumor sites. Nevertheless, it faces challenges such as inadequate bioavailability and biodistribution, which hamper its antitumor efficacy (Yokoda et al., 2017). The implementation of nanomedicines can be considered an effective strategy to provide shielding for OVs (Figure 5A). Erythrocyte–liposome hybrid nanovesicles have been demonstrated to fully shield OVs while preserving their structural integrity, thereby preventing neutralization and prolonging circulation following intravenous injection (Huang et al., 2022). Thiolated chitosan nanovesicles functionalized with hyaluronic acid have been adopted to encapsulate the Newcastle disease virus and oral measles vaccine strain (Kousar et al., 2023; Naseer et al., 2023). These nanomedicines sheltered OVs from antibody-mediated clearance and achieved sustained release, active targeting, and receptor-mediated endocytosis. The cationic gold NP coating conferred enhanced internalization and replication capacity to the virus while preventing detrimental blood factor binding (Man et al., 2022).

Figure 5.

Schematic diagram of the mechanism of nanomedicines in OV therapy. (A) Nanomedicines confer protection to the virus against neutralizing antibodies and prolong its circulation time. (B) Nanomedicines loaded with viral RNA genomes function as synthetic OVs, facilitating the virus genome amplification and virus assembly in situ via transfection, thereby inducing oncolysis. (C) The utilization of specific nanomedicines with membranolytic activity allows for the simulation of OVs. These nanomedicines undergo protonation and morphological transformation in response to changes in pH within tumor tissues, thereby activating their membranolytic components to selectively lyse tumor cell membranes. This figure is created with BioRender.com.

The use of nanomedicine to load subunits of OVs presents a promising alternative to using entire OVs, as it helps mitigate the risks associated with excessive immune activation (Diep et al., 2022). As an example, lipid-based NPs have been utilized as synthetic OVs, wherein the viral RNA genome is encapsulated. Following internalization, they subsequently facilitate in situ formation of OVs, leading to oncolysis while evading neutralizing antibodies and allowing for repeated intravenous administration (Kennedy et al., 2022; Figure 5B). Additionally, engineered protein-based nanomedicine derived from the self-assembly of fusion proteins of EGFR-specific repebody and apoptin demonstrates active targeting and selective oncolysis capabilities (Lee et al., 2017). These nanomedicines offer a feasible platform for the systematical delivery of active tumor-selective oncolytic proteins.

Membranolytic nanomedicines with an amphiphilic structure, comprising cationic and hydrophobic moieties, have been utilized to perform a function similar to that of conventional OVs (Park et al., 2018; Figure 5C). As a representative example, Liu et al. (2022c) designed a library of ‘proton transistor’ nanodetergents (pTNTs). In response to subtle pH changes within tumor tissues, pTNTs under went a rapid transition in their protonation state, resulting in a morphological transformation and activation of the membranolytic components. This unique mechanism allowed pTNTs to selectively lyse tumor cell membranes while minimizing toxicity to normal tissues. A pH-sensitive polymer NP composed of poly(ethylene glycol)-poly(2-azepane ethyl methacrylate) was designed analogously (Yu et al., 2023). These polymer NPs maintained their aggregated morphology without exhibiting any cytotoxic effects. Upon protonation in TME, they disassembled into cationic-free chains or smaller cationic NPs, initiating potent membrane-disruptive activity.

Nanomedicines in immune combination therapy

Low immunogenicity of tumors and immunosuppressive TME contribute to the intrinsic resistance of immunotherapy. In the context of combination therapy, there is a growing concentration on integrating ICD with tumor immunotherapy as a universal strategy to address immune resistance and synergistically enhance therapeutic efficacy. ICD refers to a specific process of tumor death followed by the secretion of antigens, proinflammatory factors, and damage-associated molecular patterns, thereby enhancing the immunogenicity and exerting an adjuvant effect (Qi et al., 2021). This mechanism effectively converts the previously ‘cold’ TME into a ‘hot’ one, thereby improving immune infiltration and bolstering tumor immune responses (Ahmed and Tait, 2020).

Nanomedicine offers a versatile platform to harmonize multiple modalities, even in a spatiotemporally controlled manner. Therefore, the use of nanomedicine in combination therapy has the potential to address the limitations of monotherapy and enhance efficacy (Li et al., 2023a). In the subsequent section, we primarily discuss the application of nanomedicines in combining tumor immunotherapy with ICD-inducing therapies, such as PTT, PDT, chemotherapy, and radiotherapy.

Combination of immunotherapy and PTT

PTT involves the use of photothermal agents to induce hyperthermia, leading to destruction of the cell membrane, damage to the cytoskeleton, and inhibition of DNA synthesis, ultimately resulting in apoptosis of cancer cells (Huang et al., 2021b). It has been verified that PTT can improve T-cell infiltration and reduce the number of Tregs, thereby increasing tumor sensitivity to ICBs (Ma et al., 2019). Inorganic photothermal agents such as gold, carbon, sulfide metallic, and black phosphorus can be engineered as nanocarriers for combination therapy (Huang et al., 2021b). As an example, novel immunological gold NPs were synthesized intracellularly and exocytosed as vesicles by murine melanoma cells. Subsequently, these gold NPs, which retained the original tumor antigens, were internalized and secreted by DCs in vitro, thereby functioning similarly to DC vaccines upon injection and mediating PTT as well (Zhang et al., 2019a). Ren et al. (2021) devised self-assembled nanodots to orchestrate cascade reactions, encompassing starvation, chemotherapy, CDT, and PTT. Building on the foundation of anti-CTLA4 checkpoint blockade, the cascade reaction significantly enhanced ICD, facilitated the infiltration of CTLs into distant tumors, and effectively eliminated primary tumors with improved tumor penetration. An MSN-based nanoplatform integrated with a photothermal agent polydopamine and OVA demonstrated remarkable efficacy with a 75% cure rate in B16-OVA melanoma tumors following a single injection and a single round of PTT (Huang et al., 2021a).

Combination of immunotherapy and PDT

PDT involves the activation of photosensitizers through the absorption of excitation light photons. These activated photosensitizers can then interact with endogenous substances or molecular oxygen to generate ROS and singlet oxygen, ultimately resulting in necrosis and apoptosis (Yuan et al., 2021). In addition, the antitumor vascular effect of PDT leads to tumor death by depriving the tumor of oxygen and nutrients (Kong and Chen, 2022). Hypoxia induced by PDT triggers the upregulation of hypoxia-inducible factor 1α, which subsequently increases PD-L1 levels. This elevation in PD-L1 expression enhances the antitumor effects of PDT when combined with ICBs (Yuan et al., 2021). For example, the use of mesoporous NPs to facilitate combination therapy involving IDO-derived peptide nanovaccines, PDT, and a PD-L1 inhibitor resulted in significant accumulation within tumor tissue and a synergistic capacity to induce ICDs. This versatile nanoplatform triggered robust systemic antitumor immunity and effectively delayed the progression of metastatic spinal cancer (Wang et al., 2021c). Furthermore, modification of anti-PD-L1 antibodies on photoresponsive polydopamine NPs enhanced NP binding to cancer cells and subsequently induced a more potent photothermal anticancer effect (Le et al., 2019). Besides, these NPs demonstrated the ability to capture antigens and function as in situ vaccines following PDT-induced ICD, providing long-lasting protection against tumor recurrence. The self-assembled micelles resulting from the photosensitizer Ce6 conjugated to polysaccharide hyaluronic acid functioned as a convenient and light-responsive delivery platform to orchestrate PDT and immunotherapy (Wu et al., 2021). Upon encapsulation of IDO inhibitors, these nanomedicines significantly suppressed triple-negative and poorly immunogenic 4T1 breast cancer.

Combination of immunotherapy and chemotherapy

Chemotherapy has the ability to directly deplete immune-suppressive cells, bolster effector T cells by modulating related cytokine levels, and induce TSA exposure as well as death receptor expression, rendering tumor cells more susceptible (Wu and Waxman, 2018; Yu et al., 2019). Operating as a negative feedback mechanism, PD-L1 undergoes transcriptional upregulation in response to activated NF-κB and various proinflammatory cytokines following chemotherapy. This adaptive response serves to bolster the efficacy of PD-1/PD-L1 inhibitors (Antonangeli et al., 2020; Yamaguchi et al., 2022). A nanomedicine composed of doxorubicin, photosensitizer, and cleavable peptide was engineered to mediate photochemotherapy to effectively deplete immunosuppressive cells such as Tregs and myeloid-derived suppressor cells, as well as remodel TME via ICD (Choi et al., 2021). When coordinating with PD-L1 blockades, these nanomedicines significantly enhanced the immune responses leading to the complete regression of tumors. Through the co-delivery of siCD47, siPD-L1, and camptothecin using nanomedicines developed by Zhang et al. (2023b), TME reversion was facilitated via simultaneous ICD and immune checkpoint molecule downregulation, resulting in improved infiltration of CD68⁺ macrophages and CD4⁺ and CD8⁺ T cells.

Despite the immunoregulatory effect of chemotherapy, which has been widely employed to orchestrate ICBs clinically, chemoresistance remains a major obstacle. A diverse range of NPs have been engineered to reverse chemoresistance by mitigating hypoxia in TME, regulating intracellular homeostasis, and inducing the differentiation of cancer stem cells (Jiang et al., 2022; Wang et al., 2022a; Shen et al., 2023). Jiang et al. (2021) synthesized tumor homing-penetrating peptide-modified nanomedicines loading copper tetrakis(4-carboxyphenyl)porphyrin and paclitaxel. These nanomedicines effectively depleted endogenous glutathione and downregulated P-glycoprotein expression in combination with PD-1/PD-L1 blockades, collectively overcoming chemoresistance and activating an immune response. A metal–phenolic hybrid NP composed of tannic acid and Fe³⁺ has been employed to deliver paclitaxel (Cheng et al., 2023). Upon internalization by tumors, these NPs depleted adenosine triphosphate (ATP) while disassembling, which suppressed ATP-dependent drug efflux and released paclitaxel. Coordinating with PD-1/PD-L1 blockades and PTT, these NPs alleviated chemoresistance and inhibited tumor progression.

Combination of immunotherapy and radiotherapy

Radiotherapy has the potential to induce DNA damage and facilitate tumor eradication through the use of high-energy ionizing radiation and generated ROS. Additionally, it has been observed that localized treatment of high-dose radiotherapy can trigger systemic immune responses, which contribute to the management of distant metastases, known as the abscopal effect (Herrera et al., 2017). Furthermore, low-dose radiation can promote transient tumor inflammation, recruit DCs, and activate effector CD4⁺ predominantly to execute a cytolytic transcriptional program, rendering them susceptible to immunotherapy (Herrera et al., 2022). Yu et al. (2022a) developed DC vaccines loaded with whole antigens based on ovalbumin-biomineralized NPs. Consequently, these NP-based DC vaccines, in synergy with radiotherapy, enhanced the infiltration of CTLs, improved OVA-specific immunoglobulin G levels, and reduced the percentage of Treg cells. A glutathione-modified nanomedicine coated with fusing membranes of tumor cell membranes and bacterial outer membranes was constructed to coordinate tumor vaccines and radiotherapy (Pan et al., 2022a). In comparison to the efficacy of sole nanomedicines, the incorporation of radiotherapy significantly increased the ratio of M1 macrophages and CD8⁺ T cells, while upregulating the IL-6 and IFNγ level, thereby highlighting the pivotal role of radiotherapy in amplifying the immune response.

Furthermore, the nanomedicine-mediated TME remodel contributes to radioresistance reversion. For instance, lipid-modified manganese diselenide NPs have demonstrated the capability of releasing Mn²⁺ in TME and generating ROS to augment radiosensitivity (Li et al., 2024a). Additionally, the ROS-activated cGAS–STING pathway in conjunction with cytokine secretion improved by Se⁻ contributed to a potent immune response. Analogously, hollow MnO₂ NPs loaded with a PI3Kγ inhibitor were utilized to reverse immunosuppressive TME and achieve hypoxia-alleviated radiotherapy through Mn²⁺-based catalyzing of oxygen synthesis (Guan et al., 2022). When combined with PD-L1 blockade, these NPs significantly inhibited locally residual and distant metastatic tumors. In light of the excessive accumulation of reduced glutathione leading to radioresistance, Song et al. (2024) developed a polymer-based nano-prodrug capable of delivering cinnamaldehyde and all-trans retinoic acid simultaneously in vivo, with the specific aim of depleting glutathione, disrupting redox homeostasis, and enhancing ferroptosis. Subsequently, potent systematic immune responses were elicited by radiotherapy, resulting in tumor suppression when combined with anti-PD-1 therapy.

The utilization of nanomedicine-based immune combination therapy represents a prominent research trend, demonstrating the capacity to reverse immunosuppressive TME and enhance immune responses. The rational design of nanomedicines also exhibits potential in overcoming radio/chemoresistance, thereby further contributing to immune combination therapy. However, a limited understanding of the molecular mechanisms underlying the action of combined drugs presents a significant challenge to rational nanomedicine-based combination therapy. Random combinations of different treatments may exacerbate adverse reactions and induce unexpected cross-resistance, thereby compromising the efficacy of immunotherapy (Haas et al., 2021). Therefore, the identification and mechanistic exploration of tumorigenesis, immune characteristics of TME, treatment response, and resistance development are crucial for informing judicious and precise drug/therapy combinations, thus advancing the development of corresponding nanomedicines (Paudel and Quaranta, 2019; Tutuncuoglu and Krogan, 2019).

Clinical applications of nanomedicines

The field of nanotechnology has significantly advanced the diagnosis, treatment, and prognosis of various diseases, demonstrating a promising potential for widespread clinical application. It is reported that nanomedicines applied in clinical oncology have captured ∼35% of the total market share (Gadekar et al., 2021). The global nanomedicine market is experiencing continuous growth and is projected to reach a value of US 350.8 billion by 2025 (RitaBosetti and Jones, 2019). The FDA has approved multiple antitumor nanomedicines, primarily based on liposomes, polymeric micelles, and albumin NPs for marketing. The majority of ongoing clinical trials are focused on exploring these nanomedicines for new indications and multidrug combination therapy (Huang et al., 2020b).

The integration of nanomedicine contributes to enhanced safety and favorable efficacy compared to traditional formulations of antitumor agents. A direct comparison between conventional docetaxel and CPC634, an innovative formulation of polymeric micelles cross-linked with docetaxel, revealed that CPC634 exhibited distinct pharmacokinetic profiles with a remarkable 461% increase in intratumoral total docetaxel concentration and reduced risk of neutropenia (Atrafi et al., 2020). Polymeric micellar paclitaxel combined with cisplatin resulted in an objective response rate of 50%, a treatment-related serious adverse event incidence of 9%, and a significant increase in progression-free survival by 1.1 months during the treatment of advanced non-small-cell lung cancer, surpassing solvent-based paclitaxel (Shi et al., 2021). Additionally, several innovative nanomedicines validated in preclinical research have successfully entered the clinical trial stage. AZD2811 refers to a polymeric nanomedicine encapsulating a selective inhibitor of AURKB activity, which has completed a phase I study for advanced solid tumor treatment, demonstrating manageable adverse events and preliminary antitumor efficacy with a stable disease rate of 45.1% (Johnson et al., 2023). A novel formulation utilizing albumin-bound rapamycin NPs, known as nab-sirolimus, completed a phase II clinical trial with an impressive overall response rate of 38.7% and a median duration of response over 3 years and was approved by the FDA for metastatic or locally advanced perivascular epithelioid cell tumors in 2021 (Wagner et al., 2021, 2024).

Despite extensive preclinical research on nanomedicine-mediated tumor immunotherapy and the development of various intelligent delivery systems, only a small fraction of nanomedicine-based immunotherapy progressed to the clinical stage with emphasis on the advancement of cancer nanovaccines and related combination therapies (NCT04573140). A noteworthy illustration is the utilization of nanovaccines loaded with New York esophageal squamous cell carcinoma-1 (NY-ESO-1). NY-ESO-1 exhibits expression in a wide variety of tumor types, while being restrictedly expressed in germ cells and placental cells, thus presenting a promising target for nanovaccines (Thomas et al., 2018). PLAG-based nanovaccines, encapsulating both NY-ESO-1 antigen peptides and threitolceramide-6, are currently undergoing phase I clinical trials (NCT04751786). In a separate phase I clinical study involving advanced or recurrent esophageal cancer, it was reported that NY-ESO-1 nanovaccines, in combination with poly-ICLC, elicited a robust antibody immune response while minimizing toxicities (Ishikawa et al., 2021). Furthermore, the collaboration between cognate antigen-recognizing TCR-T cell therapy and the Pullulan nanovaccine loading long peptide antigens containing the NY-ESO-1 epitope resulted in stable disease duration over 2 years, accompanied by the enduring presence of TCR-T cells in one patient (Ishihara et al., 2023). Personalized vaccines represent a significant area of research that relies on nanomedicines, which have the capability to target multiple neoantigens simultaneously in order to induce a robust immune response (Vormehr et al., 2019). A phase I clinical trial is currently underway for a DOTAP liposome-based autologous total tumor mRNA vaccine, with the aim of addressing early melanoma recurrence following anti-PD-1 therapy (NCT05264974). Another case in point is an mRNA-lipoplex neoantigen vaccine, derived from the autologous resected pancreatic ductal adenocarcinoma tumors, successfully completed a phase I clinical trial (Rojas et al., 2023). This result indicates these autogene nanovaccines elicited potent T-cell responses targeting 24% of vaccine-encoded neoantigens and effectively prolonged the time to tumor recurrence coordinating with a four-drug chemotherapy regimen (mFOLFIRINOX) and atezolizumab.

Ongoing clinical trials have revealed improved characteristics of conventional antitumor agents when formulated as nanomedicines, while also verifying the efficacy of some novel nanomedicines. Within the domain of tumor immunotherapy, utilization of nanomedicines is primarily restricted to their application in developing nanovaccines. Nevertheless, it should be emphasized that, despite extensive preclinical investigations focusing on intricate designs for versatile nanomedicines, it is primarily those with relatively uncomplicated constructs and thorough characterization that have progressed to clinical stages. Moreover, many of these nanomedicines failed to demonstrate satisfactory efficacy or raised safety concerns in clinical settings. The circumstances necessitate further endeavors to investigate the influence of physical and chemical fundamental parameters of nanomedicine on overall behaviors, which play an essential role in the further refined design of nanomedicines with the potential for clinical translation.

Conclusions and perspectives

Nanomedicines have been widely utilized in the field of tumor immunotherapy through rational design and modification, demonstrating the capability to adapt to various delivery requirements and maximize therapeutic efficacy while minimizing side effects. In order to further enhance the rational design of nanomedicines for effective tumor immunotherapy and their clinical translation, it is imperative to conduct in-depth investigations into the correlation between the physicochemical properties of nanomedicines and biological responses. A wider range of accurate models are expected to be established in order to explore and quantify nanomedicine behavior within the biological environment. A comprehensive evaluation of differences and relevance between human and animal species is urgently needed in preclinical research, which facilitates suitable animal model selection to enhance the potential of clinical translation. Additionally, mathematical and computational modelling requires further refinement through the integration of supporting data to accurately simulate human tumor models and predict nanomedicine behavior, thereby facilitating improved adjustment of nanomedicine parameters (Moradi Kashkooli et al., 2021). The development of customizable nanomedicines tailored to individual characteristics, termed as precise healthcare, holds significant promise in addressing the challenges posed by patient heterogeneity and expediting the clinical translation of nanomedicine. However, precise healthcare based on nanomedicine is still in its nascent stages and necessitates further investigation into disease progression, molecular mechanisms, and the development of robust analytical models (Han et al., 2020). The precise manipulation of nanomedicines is somewhat limited by the inherent characteristics of specific nanomaterials and the constraints imposed by synthetic methods (Nakamura and Ohta, 2024). Therefore, it is crucial to further optimize synthetic techniques and develop a universal nanoplatform for future clinical implementation of precision healthcare.

This review initially provides a comprehensive overview of representative types of NPs. Subsequently, a detailed description is presented of the current status of tumor immunotherapy utilizing nanomedicine, along with an introduction to their clinical application status. Finally, the future research direction of nanomedicine is prospectively discussed. It is believed that ongoing researches into the interaction mechanisms between nanomedicines and the biological environment contribute to further refinement in the rational design of nanomedicines. This will facilitate advancements in precise healthcare and ultimately lead to clinical benefits for a broader patient population.

Funding

This work was supported by grants from the National Science Foundation for Excellent Young Scholars (32122052), the National Natural Science Foundation Regional Innovation and Development (U19A2003), and the National Natural Science Foundation of China (82273297).

Conflict of interest: none declared.

Author contributions: X.W. and M.L. offered a significant guidance and critically reviewed this manuscript. Z.G. and D.W. drafted the manuscript and made the figures and table for the manuscript, contributing equally to the work. All authors reviewed and agreed on the final manuscript.