Introduction

Chronic liver disease (CLD) is a continuous and progressive pathological condition that progresses from initial fat accumulation to hepatitis and liver fibrosis, with end-stage fibrosis known as cirrhosis, which is highly susceptible to hepatocellular carcinoma (HCC) [1]. Approximately 12% of the global population (800 million people) suffer from liver disease and causing 2 million deaths each year [2]. Cancer is a worldwide threat to public health and HCC is the second leading cause of cancer death [3]. Is cancer curable? Almost all CLDs have provided convincing evidence confirming the reversibility of liver fibrosis and in clinical trials, in patients with chronic viral hepatitis and patients with advanced disease, timely "braking" interventions can subside fibrosis, which may be the last straw in the treatment of cancer [4,5,6].

The liver is highly complex and consists of two different cell entities, parenchymal cells, and non-parenchymal cells. Parenchymal cells include hepatocytes (60–70%) and cholangiocytes and account for most of the metabolic liver functions. While the non-parenchymal cells constitute 30–40% of total liver cells, like LSECs, HSCs, KCs, and other immune cells, playing a central role in the physiological processes of the liver [7]. The liver microenvironment, which fosters the survival and activity of liver cells, plays an important role in maintaining the normal structure and physiological function of the liver. The homeostasis of the liver microenvironment is disrupted during liver fibrosis development, causing hepatocyte damage, LSECs capillarization, HSCs activation, macrophage polarization, and immune cell suppression, and changing the cell–cell and cell–matrix interactions, which eventually form the hepatic fibrotic microenvironment [7, 8]. Recent studies have shown that modest prognostic performance (area under the receiver operating characteristic curve from 0.54 to 0.71) of five indirect markers of fibrosis (aspartate aminotransferase [AST]–to-platelet ratio index [APRI], Fibrosis-4 Index [FIB-4], BARD, Forns, NAFLD score [NAS]) [9] and direct markers-Liver Fibrosis test (LF) [10] to predict future development of cirrhosis and severe liver disease in the general population. And liver fibrosis can be assessed with relatively high accuracy noninvasively by serological tests, transient elastography, and radiological methods. These modalities may be utilized for screening for liver fibrosis in at-risk populations [11]. Nanoparticle (NPs) delivery systems have been widely studied as a drug delivery strategy in drug research and the liver targeting of NPs may be some of the nanomaterials beneficial for liver disease therapy [12], as shown in Fig. 1. NPs have diverse compositions, such as metallic NPs including metal (Ag and Au nanoparticles) and metal oxide (MOx) NPs including transition-metal oxides (TMOs, e.g., SiO2, ZnO, and TiO2), carbon NPs including 1D carbon nanotubes (CNTs) and 2D graphene-based NPs (FPL, and GO), cellulose nanocrystal (CNC) and cellulose nanofiber (CNF), Fluorescent NPs (quantum dots, CDs, Organic fluorophores), and organic NPs including lipid NPs, liposomes, and polymer NPs.

Fig. 1
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The major intrinsic properties of NPs and cellular uptake by the major liver cells

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Table 1 Preclinical NPs for the treatment of liver fibrosis
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Although these NPs have a challenging and lengthy process, such as systemic circulation, drugs accumulation in the lesion, deep penetration, and intracellular release of drugs, the liver is one of the major aggregation organs for NPs, conventional NPs are recognized as foreign bodies, and rapidly captured by the reticuloendothelial system (RES) through the regulation of plasma proteins after administration, but the liver targeting NPs may serve as a beneficial nanomaterial for liver disease therapy [12], as shown in Fig. 2. As NPs move along the sinusoid, they will come into contact with sinusoidal endothelial cells, Kupffer cells (KCs), T cells, and DCs. Depending on their physicochemical properties, NPs have better access through fenestrae to enter the space of Disse and contact with hepatocytes. The smaller NPs may transcytose through the hepatocytes and enter the bile duct through bile canaliculi. Conventional NPs are captured by the RES. Larger size, negatively charged, or hydrophilic NPs are preferentially swallowed by KCs via phagocytosis; NPs less than 200 nm NP or with negative surface charge or hydrophobicity tend to be taken up by endothelial cells through clathrin-mediated endocytosis with a high exposure dose or long time. NPs less than 50 nm NP or hydrophilic NPs could be captured by stellate cells. Smaller NPs with positive surface charge or hydrophobic NPs are preferentially taken up by hepatocytes through clathrin-mediated endocytosis.

Fig. 2
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Interactions of NPs uptake and elimination in the liver during systematic circulation after NPs exposure

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Table 2 Preclinical NPs for the treatment of liver fibrosis
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Hence, we reviewed the latest advances in remodeling the hepatic fibrotic microenvironment with emerging monotherapies, with particular attention to remodeling immune regulation, metabolic reprogramming, ECM deposition, and hypoxia-induced vascular production in the hepatic fibrotic microenvironment. Finally, the nano-advantages and challenges of engineered NPs targeting APCs or directly targeting T cells for immunotherapy of liver fibrosis were highlighted in this review.

Engineered NPs regulated immunosuppression-associated microenvironment

The immune system is a complex network including lymphoid organs, cells, and cytokines [13]. RES uptake and immune cell suppression are considered the main immune-related effects. In the liver, the RES, composed of LSECs and KCs, is the primary site of exposure to microbial antigens and plays a vital role in the uptake and clearance of soluble antigens from the hepatic sinusoids, serving as a guard against microbial invasion and maintenance of hepatic homeostasis [14]. Once fibrosis starts, LSECs change their phenotype (from fenestrations to capillaries) and then they open windows and the surface gradually shrinks to form an organized basement membrane, that is, "hepatic sinusoidal capillarization". In addition, LSECs serve as gatekeepers of the hepatic microenvironment and as platforms for innate or adaptive immune cells to stay in the hepatic sinusoidal microenvironment. This is important for maintaining systemic immune homeostasis [15].

LSECs-related immunosuppression-associated microenvironment

In the innate immune response, LSECs have an effective function by directly participating in the suppression of activated CD4 + T cells [16], or by expressing major histocompatibility complex (MHC) class I and II molecules presented to CD8 + T cells and promoting the activation of regulatory T cells (Tregs) [17]. In addition, LSECs express a variety of pattern recognition receptors including the toll-like receptor (TLR) family, scavenger receptors (SR-A, SR-B, and SR-H), and mannose receptors (MR) that produce inhibitory acquired immune responses. LSECs regulate adaptive immune responses directly by presenting antigens to T cells and also regulate natural killer T cells (NKT cells) by expressing CXCL16, and the cell surface ligand for CXCR6 [18]. Hepatic macrophages account for 90% of the total macrophages in the human body, and they are very plastic and adapt their phenotype according to signals derived from the hepatic fibrotic microenvironment [19]. They are divided into infiltrating macrophages and liver-resident macrophages[20]. Liver-resident macrophages, called KCs are self-renewed, resident, and non-migratory [19]. Liver injury triggers KCs activation, leading to inflammatory cytokine and chemokine release. This fosters the infiltration of monocytes into the liver, which gives rise to the large number of inflammatory monocyte-derived macrophages [21] Moreover, KCs promote T cell-mediated hepatitis development by producing CXCL10 and limiting the permeability of hepatic LSECs [22]. The macrophage pool of the liver can be rapidly expanded by infiltrating phagocytes that mainly originate from peripheral blood marrow/monocyte-derived macrophages [21], a few from peritoneal macrophages [23], and splenic macrophages [24]. In mice, two major populations of circulating monocytes exist Ly-6C high (Ly-6Chi) and Ly-6C low (Ly-6Clo) expressing monocytes. Whereas the Ly-6Chi monocytes express inflammatory chemokine receptors (like CCR2), pattern-recognition receptors, and cytokines [25]. The bone marrow is the primary source of the (relatively immature) Ly-6Chi monocytes [26], whereas the spleen serves as a reservoir for Ly-6Clo monocytes, the production of TNF-α, IL-6, and IL-10 increased significantly in hepatic splenic macrophages and migrate from bone marrow to the liver via the spleen [27]. As a consequence of tissue injury, KCs and other liver cells (HSCs, hepatocytes) secrete chemokines like CCL2 that provoke the massive infiltration of Ly6Chi monocytes into the injured liver [28]. This provides a rapid and transient mechanism to expand the macrophage pool in the liver by inflammation-prone phagocytes. Together, they form a "profibrogenic environment" in which immune homeostasis is disrupted, which may explain the refractory nature of immunotherapy for liver fibrosis, as shown in Table 1.

Polymeric micelles (PMs) as drug delivery vehicles have specific targeting and high stability in vivo as illustrated in Fig. 3. Scavenger receptors form a superfamily of membrane-bound receptors, and in vitro studies have shown that anionic NPs modified with scavenger receptor stabilizer-2 (stab2) receptor ligands target naturally tolerant LSECs and generate Tregs, thereby suppressing antigen-specific immune responses [29] and which also leads to selective deletion of single blood vessels in zebrafish embryos, with important clearance of lipoprotein B-containing lipoproteins in zebrafish [30]. Hyaluronic acid (HA) is a naturally occurring ligand and encapsulated micelles that show sustained drug release and low cytotoxicity for targeting LSECs, with over 90% of HA in the blood that is absorbed and metabolized by LSECs [31] LSEC-targeting and fenestrae-repairing nanoparticles (named HA-NPs/SMV) rapidly released SMV and exerted a fenestrae-repairing function, providing an antifibrotic therapeutic regimen. [32]. Studies have shown that coating positively charged PMs consisting of poly(L-lysine)-block-poly(L-lactide) (PLys-b-PLLA) AB diblock copolymers with anionic HA by polyion complex (PIC) formation target specific interaction between LSECs and KCs, thereby increasing the toxic T-lymphocyte/Treg cell ratio and then cause immune inflammation [33]. Poly (lactic-co-glycolic acid) (PLGA) has been used in many long-acting drug formulations approved by the US Food and Drug Administration (FDA) [34]. NPs decorated with stab ligands and PLGA target naturally tolerant LSECs are capable of producing Tregs to inhibit antigen-specific immune responses [33].

Fig. 3
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The NPs in LSECs capillarization-mediated immunosuppression-associated microenvironment of liver fibrosis

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Macrophages-related immunosuppression-associated microenvironment

Activated macrophages can release cytokines, which can affect the adaptive immune response [35]. It was illustrated in Fig. 4 that MR directly promotes the pro-inflammatory activation of macrophages and triggers inflammation [36]. Mannose-modified albumin NPs have the potential to deliver TGFβ-siRNA to CD206 + macrophages as an anti-fibrotic strategy [37]. A stable nucleic acid–lipid particle delivery system of mannose-modified HMGB1-siRNA (mLNP-siHMGB1) targets hepatic macrophages via mannose receptor-mediated targeting, thereby silencing HMGB1 protein expression and inhibits the activation of HSCs for the treatment of liver fibrosis [38]. Mannose-modified trimethyl chitosan-cysteine (MTC)-coupled NPs as efficient polymeric carriers for oral TNF-α siRNA, and a dextran-based siRNA carrier system, BG34-10-Re-I/siRNA, was also developed for macrophage-targeted siRNA delivery [39]. Carboxymethyl chitosan (CMC) is a promising drug-release polymeric carrier with biocompatible, biodegradable, and easily accessible features. CMC reduces host immune response in an experimental mouse model of CCl4-induced chronic liver injury [40]. Phosphatidylserine (PS) is a phospholipid with a negatively charged head that is normally found in the inner leaflet of the cell membrane. PS-containing NPs are commonly used to mimic apoptotic cells and can specifically modulate macrophage function and enhance the targeting ability of macrophages [41], PS-modified nanostructured lipid carriers were further designed in some previous studies to improve hepatic delivery efficiency and its bioavailability, thereby reducing liver fibrosis and collagen fiber deposition in vivo [42]. The scaffolds crosslinked with nano-graphene oxide show high resistance to enzymatic degradation via direct inhibition of MMPs activity and increased M2-like macrophage polarization, which reduces graft-elicited inflammation (Table 2). Overall, nano-graphene oxide offers an alternative for donor organs [43].

Fig. 4
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The NPs in macrophages polarization-mediated immunosuppression-associated microenvironment of liver fibrosis

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Engineered NPs regulated metabolic reprogramming-associated microenvironment

Liver injury stimulates the transdifferentiation of quiescent hepatic stellate cell HSCs to proliferative, migratory, and fibrotic myofibroblastic (MFs) [44]. The short-term accumulation of MFs is beneficial for liver regeneration, however, long-term excessive accumulation results in progressive fibrosis, repair defects, and increase risk and mortality from cirrhosis and liver cancer [45]. The acquisition of MFs phenotype is energy-intensive, whereas reprogramming of HSCs in metabolism is similar to that of highly proliferative cancer cells, and orchestrating the reprogramming of HSCs is a novel therapeutic target for fibrosis therapy [46, 47], including.

  1. (1)

    Enhanced aerobic glycolysis [48]. Elevation in glycolysis is related to an increase in glucose transporter proteins, including GLUT1, which is highly overexpressed in cancer cells [49] In addition, an increase in glycolysis is accompanied by a shunt of central carbon metabolites from the citric acid cycle, including increased expression of pyruvate dehydrogenase kinase 3 (PDK3), which promotes lactate production. A similar phenomenon is called the Warburg effect in cancer cells [50]. Furthermore, pyruvate kinase M2 (PKM2) represents a unique link between aHSCs and cancer cells that promote aerobic glycolysis [51].

  2. (2)

    Upregulation of glutamine catabolism [52]. Glutamine metabolism has been identified as an additional source of ATP in HSCs. Liver samples from patients with nonalcoholic steatohepatitis (NASH) and advanced fibrosis [53] and a mouse model of liver fibrosis [54] have shown that the proliferation of HSCs is heavily dependent on glutamine metabolism [52]. Metabotropic glutamate receptor-5 (mGluR5) production of 2-arachidonic acid glycerol (2-AG) in HSCs activates hepatocyte cannabinoid receptor-1 (CB1R)-mediated neoadipogenesis [55].

  3. (3)

    Fatty acid catabolism [56]. Compared to the resting HSCs, activated HSCs have abundant mitochondria, and the requirement to maintain the phenotype of MFs still needs the energetic contribution of oxidative phosphorylation (OXPHOS). It has been shown that mitochondrial uncoupling inhibits the activation of HSCs in vitro, despite increased glycolysis [57]. The metabolism of lipid droplets that provide fatty acids for mitochondrial β-oxidation (FAO) plays an important role in lipid metabolic pathways [58]. Similarly, in cancer, FAO survives oxidative stress and nutrient deprivation [56].

HSCs-related metabolic reprogramming-associated microenvironment

It was illustrated in Fig. 5 that the HSCs expressed the mannose-6-phosphate/insulin-like growth factor II (M6P/IGFII) receptor, and M6P-modified albumin activates HSCs in the fibrotic liver, blocks glutamine (GLN) catabolism by mediating the Hedgehog signaling pathway Glutaminases including GLS (glutaminase), aspartate aminotransferase (GOT1) and glutamate dehydrogenase (GLUD1) and inhibits myofibrillar activity [59]. GLN metabolism is an important component of metabolic reprogramming. GLN can be converted to α-ketoglutarate (α-KG) to provide carbon for the TCA cycle, or to other NEAAs via transaminases (GOT1 and GOT2). GLN can also be converted to glutamate and pyrroline-5-carboxylic acid (P5C) to stimulate collagen biosynthesis [60]. HSCs have multiple vitamin A (VA)-rich lipid droplets in the cytoplasm, which are the primary sites for retinoid derivatives storage in vivo. A study has synthesized a novel VA-Myrj52 ester conjugated solid lipid NPs (VA-SLNs) using all-trans retinoic acid and hydrophilic emulsifier (Myrj52) as targeting agents to effectively reduce peroxisome proliferator-activated receptor γ (PPARγ)/SREBPs-mediated lipid accumulation [61]. SREBPs are highly expressed to promote tumor growth, especially in the regulation of lipid metabolism [62]. In addition, chondroitin sulfate PMs target HSCs in liver fibrosis [63]. Green biosynthesis of NPs using reduced metabolites of microbial and plant-derived products is a better strategy for achieving inexpensive products that are less harmful to health and the environment compared to artificial physical or chemically manufactured NPs [64]. TGFβ signaling is involved in stimulating glycolysis and mitochondrial respiration. Inhibitory effect of curcumin/chitosan-coated green silver NPs directly bound to the fibrogenic protein TGF-β [65]. Mouse livers were decellularized to form liver hydrogels as an injectable biomaterial in the liver, which blocked the TGF-β1/Smad pathway to reduce fibrosis [66] (Table 2).

Fig. 5
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The NPs in HSCs activation-mediated metabolic reprogramming-associated microenvironment of liver fibrosis

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Immune cells related metabolic reprogramming-associated microenvironment

Regarding macrophages and KCs, restriction of their glucose and glutamine supply inhibits their secretory function [67]. Conversely, altered lipid metabolism causes KCs to accumulate cytotoxic lipids to enhance the proinflammatory phenotype [68]. The enhanced glycolytic activity, altered tricarboxylic acid cycle, and reduced ATP production in the macrophages under 100–125 nm diameter NPs made of silk, poly(lactic-ethanolic acid), or silicon consistent with a pro-inflammatory phenotype [69]. PEGylation of cellulose nanofiber (CNF) reduces macrophage-initiated inflammatory and metabolic responses, including increased glycolysis and reprogramming of the tricarboxylic acid cycle and the creatine kinase/phosphocreatine pathway [70]. Energy metabolism is also involved in the body's immune network. It has been shown that metabolic reprogramming between immune cells and cancer-associated fibroblasts (CAFs) indicated the immune status of tumors [71]. aCD3/F/AN-induced lipid metabolic reprogramming specifically activates T cells [72]. A recent study synthesizes cholesterol-modified polymeric CXCR4 inhibitor (Chol-PCX) in the form of Chol-PCX/miRNA NPs and CXCL12/CXCR4 axis disrupts the lipid metabolic network of T cells for the amplified treatment of liver fibrosis [73, 74], suggesting that nanotechnology-enabled T cell lipid metabolic reprogramming has the potential to be a new paradigm for immunometabolic therapy.

Engineered NPs regulated hypoxia-associated microenvironment

Activated HSCs lose the ability to store retinol, then they begin to proliferate and produce pro-fibrotic cytokines such asα-smooth muscle actin (α-SMA), type I, and type III collagens [44]. Whereas collagen fibers between adjacent hepatic blood sinusoids contact each other and encircle hepatocytes in a grid pattern, which weakens oxygen exchange between hepatic sinusoids and hepatocytes, therefore leads to hypoxia in the microenvironment of liver fibrosis [75]. In addition, abnormal immune inflammation leads to the release of inflammatory factors, chemokines, ROS, adipokines, and pro-angiogenic mediators [76]. Among them, intracellular NO and ROS reactions are significantly increased in extracellular matrix (ECM) subjected to peroxynitrite (ONOO-)-mediated oxidization, and MMP-2 activity, directly mediated by S-glutathionylation of its cysteine residues in the presence of ONOO(-) and by phosphorylation of its serine and threonine residues [77], as well as increased fibrosis [78]. Excessive deposition of fibrillated collagen (mainly collagen I), the main collagen of ECM, in the Disse space would greatly impede the delivery of HSCs by nanoformulations [157]. However, there are few relevant studies and in-depth studies are needed in the future.

Conclusions and outlooks

Engineered NPs are ideal tools for the application of liver fibrosis therapy. However, only a few have been successfully translated into clinical practice, mainly due to the macrophage uptake of NPs. Disulfide bonds are commonly used as intermediate linkers in the fabrication of silicon networks, and disulfide-bonded organosilicon NPs with cage-like morphology target LSECs to avoid macrophage filtration and may affect the tolerance status of intrahepatic immune cells [158]. (1) Targeting specific cell types is expected to be a useful technique, suggesting the use of nanomedicines for diagnostic, therapeutic, and prognostic integration of personalized treatment of liver fibrosis is an important future drug development direction. LNPs accumulate in the LSECs to cause activation and neutrophil inflammation. Furthermore, the modification of N-acetyl-D-galactosamine (GalNAc)-LNPs with polyethylene glycol eliminates the toxicity associated with LNPs [159]. (2) Combination therapies with different mechanisms can be used for the development of engineered nanotherapeutics. The microenvironment of liver fibrosis is the result of multiple cellular interactions upon encountering the capillaries LSEC barrier, HA-NPs/SMV rapidly released SMV and exerted a fenestrae-repairing function, which allowed more CV-NPs/siCol1α1 to enter the space of Disse to degrade deposited collagen and finally to achieve higher accumulation in activated HSCs, promoting pathological barrier-normalization [32]. (3) The biosafety of the NPs should be investigated more. Although the biocompatibility of the NPs have been confirmed in vitro or in vivo. But when they need to be transferred to the clinical trials, such as the biodistribution after the injection, or the biodegradation pathway in different organs.

In addition to traditional drug therapies, nano vaccines allow precise modulation of the composition and structure of NPs, their physicochemical properties (size, shape, function, and surface charge) as well as the dose and route of administration of nano drugs, to improve antigen presentation and strong immunogenicity. Therefore, it has become an attractive alternative or complementary therapy in the field of cancer treatment [160] and has received lots of attention in the treatment of liver fibrosis. Polystyrene NPs, PLGA, CNTs, aluminum hydroxide NPs, SiO2 NPs, carbon black NPs, and TiO2 NPs, have been shown to stimulate NLRP3-related inflammasomes [161], and liposomes, polymers, and inorganic NPs, as well as self-assembled protein NPs and virus-like particles (VLPs), are being explored as antigen carriers [160]. Furthermore, achieving subcellular localization of drug loading is critical to maximizing the therapeutic potential of a drug [162]. Carbon dots (CDs) are new fluorescent nanomaterials with negligible photobleaching, among which graphene quantum dots (GQDs) can be used for super-selective cell nuclear imaging due to their superior biocompatibility and targeting ability [163]. In addition, quantum dots (QDs) are used for imaging and drug-targeted delivery, which allow rapid absorption in the small intestine after oral administration and is highly specific targeting to LSECs or hepatocytes [164]. Moreover, graphene oxide (GO) enables efficient liver regeneration via immunomodulation [43].

Meanwhile, the hepatic fibrosis microenvironment, composed of immune cells, MFs, LSECs, HSCs, and ECM with abundant growth/signaling factors, is a unique, complex, and highly dynamic region. These diverse cell types and ECM proteins are capable of coordinating liver remodeling, hematopoiesis, regulation of immune function, and tissue regeneration. Reprogramming the tumor microenvironment (TIME) and reversing immunosuppressive strategies are currently the most beneficial modalities for cancer therapy [165]. In addition, the hepatic fibrosis microenvironment and reversal of immunosuppression are the most promising strategies for liver fibrosis treatment. Moreover, the energy utilization of immune cells differs significantly in T cells exhibiting completely different metabolic patterns depending on the activation state [166]. For example, the metabolism of naive T cells is essentially static [167], exhibiting zero proliferation, therefore, only minimal nutrient intake. Minimal glycolytic rates and minimal biosynthesis are required to maintain reliance on OXPHOS to provide ATP [168]. As it becomes metabolically activated, there is an increased nutrient uptake, enhanced glycolysis rate, synthesis, and accumulation of proteins, lipids, and nucleotides, as well as the growth and proliferation of T cells to perform killing functions [168]. Memory T cells have a similar metabolic pattern to naive T cells, maintaining a basic nutrient intake, a lower glycolytic rate, and relying on OXPHOS for ATP [169]. In addition, activated NK cells [170], neutrophils [171], M1 macrophages [172], and DCs [173] rely mainly on glycolysis for energy supply. However, DCs used mainly oxidative phosphorylation for energy metabolism at resting state. In addition, aerobic glycolysis and pentose phosphate pathway are the main metabolic modes of neutrophils [174]. More interestingly, glycolysis and mitochondrial metabolism are enhanced following the activation of B lymphocytes induced by LPS stimulation or antigenic stimulation. However, glycolysis is the main metabolism in activated B lymphocytes [175]. However, Treg cells [176] and M2 macrophages [177] mainly rely on OXPHOS (FAO) from fatty acid oxidation for energy supply. It is suggested that novel immune cell metabolic reprogramming targeting biodegradability, specific selectivity, responsive drug release, and multimodal synergistic therapy of engineered nanomaterials have broad applications in the treatment of liver fibrosis.

Nanomedicine for fibrosis offers the opportunity to enhance the anti-fibrotic immune response, achieve specificity and local amplification of the immune response safely and effectively in fibrotic tissue, and improve the rate of patients` treatment for immunotherapy, as well as reduce related side effects. Several nanoparticle-based T-cell therapies remained unexploited. For example, more studies in recent years have identified new subpopulations of immune cells [178] and these subgroups are considered to be homogeneous groups, which may be a new target for immunotherapy, and the mechanisms of these therapies need to be further understood. The ability to manufacture "generic" or "off-the-shelf" NPs using antigen diagnostics will reduce the cost burden and expand the range of patients to be effectively treated with T-cell immunotherapy compared to cell-based therapies. In addition, multi-reactive nanomedicine for immunotherapy comprehensively modulates complex pathogenic processes. Therefore, NP-mediated T-cell immunotherapy will have sustained progress in the future.