Nano-Drug Delivery to Target Macrophages

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This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10051203

Macrophages are the most important innate immune cells that participate in various inflammation-related diseases. Therefore, macrophage-related pathological processes are essential targets in the diagnosis and treatment of diseases. Since nanoparticles (NPs) can be preferentially taken up by macrophages, NPs have attracted most attention for specific macrophage-targeting.

macrophages nanoparticles nanotechnology drug-targeting inflammation inflammatory diseases

1. Introduction

Nanoparticles (NPs) have been extensively used for drug delivery in disease treatment, taking advantage of their stability, biocompatibility, blood circulation, immunogenicity, and capability to control drug release. Due to the nature of phagocytes, NPs can be preferably taken up by phagocytes in vivo, facilitating phagocyte-targeting drug delivery without influencing the function of other cells, which has become a new direction of drug delivery. Phagocytes, such as macrophages, are the most significant innate immune cells, which participate in the pathological processes of various inflammation-related diseases, making macrophages essential targets for developing novel diagnostic imaging and disease treatment. Therefore, increasing studies have used NPs for macrophage-targeting drug delivery.

2. Macrophage-Targeting Nanotechnologies

2.1. Passive Macrophage-Targeting Nanotechnologies

There are two specific-targeting approaches in the design of NP-based drug delivery systems, namely passive and active targeting (Figure 1).

Figure 1. Summary of macrophage-targeting nanotechnologies. (A) Passive macrophage-targeting. NPs accumulate in tissues through the vascular leakage. (B) Passive macrophage-targeting. NPs with different sizes preferentially accumulate in different organs. (C) Active macrophage-targeting. With various surface modification methods, NPs can specially target macrophages via recognition by receptors on macrophage membrane.

Passive targeting takes advantage of the NP pharmacokinetics, unique vascular pathophysiology, and immune responses of the targeted tissue, leading to the accumulation of NPs ^[1]^[2]. For example, large NPs (up to 500 nm) predominantly accumulate in the liver and lungs; medium NPs (10–300 nm) aggregate mainly in the liver and spleen after being opsonized and removed from the circulation; and small NPs (1–20 nm) are usually degraded by macrophages in the kidneys ^[1]^[3]^[4]. Therefore, the preference for unmodified NPs to accumulate in certain tissues has been utilized as a passive-targeting approach to deliver the payload to the macrophages. Inflammatory tissues and solid tumors are characterized by vascular leakage contributed by inflammatory mediators, cytokines, and growth factors that cause disruption of the endothelium ^[5]^[6]^[7] and, consequently, result in NP in situ accumulation. For example, Corvo et al. ^[8] intravenously injected liposomes coated with PEG into a mice model of rheumatoid arthritis and observed passive accumulation of these NPs at the arthritic sites. Thus, NPs with proper size can preferentially extravasate from the blood into the interstitial spaces and accumulate in inflammation sites or tumor tissues via the enhanced permeability and retention (EPR) effect ^[9]. Meanwhile, Keliher et al. ^[10] reported that TAMs are able to selectively capture NPs and translocate them from the periphery to the central hypoxic zone of tumor tissue. The ability of TAMs to take up NPs has been utilized in tumor imaging and quantification of TAMs in which zirconium (Zr)-labeled dextran-based NPs were applied as MRI imaging agents ^[4]. Since elevated infiltration of macrophages and lymphocytes are common in the extravascular spaces of inflammation sites and tumors (inducing excessive inflammatory responses and tissue damage) ^[11]^[12]^[13], macrophages are considered the primary therapeutic targets in inflammatory diseases ^[14]^[15], and particle uptake into macrophages could, therefore, allow the selective accumulation of NPs in the areas of inflammation ^[16]^[17].

2.2. Active Macrophage-Targeting Nanotechnologies

2.2.1. Phagocytosis-Related Cell Membrane Receptors Targeting

Active targeting can be used to enhance the selective delivery of drugs into the target cells or tissues by exploiting the specific interactions between drug carriers and targeted sites ^[1]^[18]^[19]^[20]. Currently, the most common approach to achieve active-targeting is to decorate the surface of NPs with an agent (e.g., ligand, antibody, and peptide) that can selectively interact and be recognized by the particular cell type in certain tissue ^[21]. Different receptors and lipid components on the cell membrane, thus playing a prominent role in active-targeting, for they can recognize specific agents on NPs. Moreover, compared with normal cells, pathological cells may uniquely express these receptors or express them at a different amount. Depending on the target cell and/or tissue types, various ligands, such as monoclonal antibodies, could be harnessed to the particle surface ^[22]. Thus, the active-targeting approach of NPs is based on the concept that the surface of the delivery vehicle is modified with a ligand or antigen to allow selective interaction with the target receptors ^[23]. The macrophage cell membrane surfaces contain many receptors that determine the activity of macrophages, including growth, differentiation, activation, recognition, endocytosis, migration, and secretion ^[24]. Among them, three main groups are frequently assumed: TLR, non-TLR, and opsonic receptors. Although TLRs do not participate in phagocytosis or endocytosis, they are involved in antimicrobial peptide production and innate immunity, playing a central role in recognition of pathogens and activation of innate immune responses ^[25]^[26]^[27]. Non-TLR, including the family of scavenger receptors ^[28] and the C-type lectins ^[29], are involved in phagocytosis and endocytosis. Opsonic receptors include complement receptors (integrins, such as CD11b) and Fc receptors (immunoglobulin superfamily, such as CD44), which dominate the phagocytosis and endocytosis of complement- or antibody-opsonised particles, respectively ^[30]. Those phagocytosis-related receptors are, thus, ideal structures for a macrophage-targeting therapy, which can facilitate nano-carriers to deliver therapeutic agents into macrophages selectively. As for non-TLR, for example, C-type lectin receptors (CLRs) recognize conserved carbohydrate structures, including mannose and galactose. Mannosylated liposomes have repeatedly been shown to preferentially target macrophages, enhancing cellular uptake both in vitro and in vivo ^[31]^[32]^[33]^[34]. Likewise, Lipinski et al. have decorated antibodies that specially interact with scavenger receptor (CD36, which is highly expressed on the surface of macrophages) on the surface of micelles for macrophage-targeting imaging in atherosclerosis ^[35]. Hyaluronic acid (HA), which is an unbranched non-sulphated glycosaminoglycan consisting of repeating disaccharides (β-1,3-N-acetyl-D-glucosamine and β-1,4-D-glucuronic acid), can be recognized by a large number of HA receptors on macrophages, such as Fc receptor (CD44), the receptor for HA-mediated motility (RHAMM), and several other receptors possessing HA-binding motifs ^[36]. Kamat et al. found that iron oxide magnetic NPs coated HA could be efficiently entrapped by activated THP-1 macrophages in vivo ^[37]. Tsai et al. reported a HA conjugated gold nanorod (HA-Au NR) as a drug carrier for anticancer doxorubicin (Dox) delivery, and HA significantly improved the recognition and uptake of HA/Dox-Au NRs by RAW 264.7 cells through the specific interaction with the HA receptor, CD44 on the cell surface ^[38]. Additionally, the modification effectively improved biocompatibility by switching the surface charge from positive (due to chitosan polymer) to negative (due to hyaluronate) ^[39]. To reduce the immunogenicity associated with the Fc portion, Gagne et al. coupled Fab’ fragment of the anti-HLA-DR (anti-class II major histocompatibility complex molecules) antibody rather than the entire antibody with PEG-modified immunoliposomes. Macrophages express a high level of HLA-DR, and the result showed a much more increased accumulation of modified NPs in lymphoid tissues compared with free drugs ^[40].

2.2.2. Pathogen Components-Mediated Macrophage-Targeting

In addition to components targeting phagocytosis-related cell membrane receptors, another strategy is to use pathogen-associated components to induce active-targeting, which takes advantage of the macrophage’s nature to engulf pathogens. Chavez-Santoscoy et al. decorated galactose and di-mannose on the surface of polyanhydride NPs to provide pathogen-like properties to target CLRs on alveolar macrophages ^[41]. Mannosylated fluorescent phenylboronic acid-containing NPs were also selectively taken up by murine RAW 264.7 macrophages, which were used as cell imaging agents ^[42]. More importantly, according to some in vivo studies, mannose significantly increased the uptake of gelatin NPs by macrophages in the liver, lymph nodes, and lung, compared with pure gelatin NPs ^[39]. Dextran sulphate, derived from certain lactic acid bacteria, is constituted by a linear glucose chain with one sulphate group per glucose unit ^[43]. Dextran is reported to be recognized by scavenger receptor class A on macrophages ^[44]^[45]^[46]^[47], which is, therefore, frequently used as decoration on NPs to enhance the specificity for targeting macrophages ^[10]^[48]. Keliher et al. has introduced a crosslinked, short-chain dextran nanoparticle that accumulated primarily in tissue-resident macrophages. Labeled with ⁸⁹Zr, this NP can be used as a macrophage-specific PET imaging agent to quantify macrophage inflammation levels in the diagnosis of various diseases, such as cancer, atherosclerosis, and myocardial infarction ^[10].

Despite of ligands, Ren et al. encapsuled polymer−lipid hybrid NPs into porous and hollow yeast cell wall for macrophage-targeting drug delivery. The yeast cell wall composed of natural β-1,3-D glucan, can be recognized by the apical membrane receptor, dectin-1, which has a high expression on macrophages and intestinal M cells ^[49]. Soto et al. also incorporated NPs as cores inside glucan particles (GPs), which are hollow, porous 2–4 μm microspheres derived from the cell walls of Baker’s yeast (Saccharomyces cerevisiae), taking advantage of the macrophage-targeting property of GPs. The 1,3-β-glucan outer shell provides for receptor-mediated uptake by phagocytic cells expressing β-glucan receptors ^[50]. Except for the cell wall, Gram-negative bacteria outer membrane vehicles (OMVs), which exhibit various pathogen-associated molecular patterns and immunogenic antigens ^[51]^[52] that can be recognized by macrophages, have also been used for macrophage-targeting immunomodulation ^[53]^[54]. Gao et al. compared nanoparticles coated with the membrane of OMVs from Staphyloccocus. aureus (S. aureus) with counterparts coated with PEGylated lipid bilayer, and OMV membrane coating was found to facilitate NP internalization by S. aureus-infected macrophages ^[55].

Despite membrane coating, bio-nanocapsules (BNCs) derived from pathogens could be directly used as drug carriers. For example, hepatitis B virus (HBV) envelope particles, which are 50 nm BNCs consisting of approximately 110 molecules of HBV surface antigen L protein and lipid bilayer, have been explored to specifically deliver payloads to liver cells ^[56]. Li et al. then developed mutated BNC to selectively target the non-hepatic cells and tissues in vitro and in vivo, relying on the outwardly displayed tandem form of the S. aureus protein A-derived Z domain which could bind to animal IgG Fc domains ^[57]^[58]^[59]. This protein A-derived Z domain was recently replaced by Finegoldia magna protein L-derived B1 domain and showed enhanced uptake by the murine macrophage cell line RAW 264.7 ^[60].

2.2.3. Other Chemical Compounds-Mediated Macrophage-Targeting

The folate receptor (FR) is over-expressed on the activated macrophage surface in rheumatoid arthritis ^[61]^[62]. Thomas et al. used folate, which can be recognized by FR on macrophages, to decorate NPs loaded with methotrexate for macrophages-targeting. These NPs were demonstrated to offer a practical clinical approach to improving the drug delivery and efficacy at the inflammatory site of arthritis ^[63]. Similarly, another study fabricated FR-targeting fluorescence nanoprobes to detect and quantify the extent of biomaterial-mediated inflammatory responses in vivo. They found a good relationship between the extent of the inflammation and the intensity of nanoprobe-associated fluorescence signal in tissue ^[64]. Except for arthritis, ovarian TAMs also express a high level of folate receptor-2 (FOLR2), which can be selectively targeted using G5-methotrexate (act as both a ligand and a toxin) dendrimer NPs for cancer treatment ^[65].

Phosphatidylserine (PhoS) has significant potential to selectively target macrophages and has been frequently applied in developing drug delivery systems by anchoring PhoS on NPs ^[63]^[64]^[65]^[66]. Normal cells have PhoS inside the phospholipid bilayered plasma membrane, whereas apoptotic cells bring out PhoS to the outer surface of the plasma membrane and make themselves recognized by macrophages for phagocytosis. Thus, the expression of PhoS on apoptotic cells allows for PhoS-dependent identification and engulfment by macrophages ^[66].

Brain-derived neurotrophic factor (BDNF), which is a protein belonging to neurotrophins that support neuronal cells’ growth, differentiation, and survival, can bind to two neurotrophin receptors on the cell surface: the low-affinity neurotrophin receptor p75 and the high-affinity receptor TrkB ^[67]^[68]. In the research by Talvitie, chitosan NPs were functioned by TrkB binding targeting peptides and showed more efficient binding to RAW 264.7 macrophages than pure NPs ^[69].

Heparin, which is traditionally regarded as an anticoagulant, is also reported to have macrophage binding affinity and can further act as a macrophage-targeting agent ^[70]. Its uptake by macrophages is reported to be mediated by scavenger-like receptors. Interestingly, heparin-loading reduced the toxicity of cationic NPs in the rat macrophage NR8383 cell line ^[71]^[72].

2.2.4. Strategy to Specifically Target M1 or M2 Macrophage

As previously mentioned, macrophages in inflammation sites polarize into two phenotypes depending on local stimulations. A prolonged activation or dysregulation of M1 activity is closely related to the development of chronic diseases, such as rheumatoid arthritis, delayed/non-healing wounds, psoriasis, and septic shock, which can lead to multiple organ dysfunction syndromes (MODS). Therefore, selective M1 macrophage-targeting immunomodulation has become the focus of treatment, which can avoid the side effects on other cells ^[73]. However, it is challenging to find a suitable surface molecule specifically expressed or upregulated by M1 macrophages. This is because macrophages are highly plastic cells, exhibiting different surface markers depending on the inducers from the different microenvironments ^[74]. Recently, M1-specific and M2-specific surface marker screening have been performed, using mice and human macrophages exposed to their respective inflammatory stimulus (M1: IFN-γ and LPS, M2: IL-4) ^[75]. According to the study, the expression of two receptors (CD64, CD14) was increased in both mice and human M1 macrophages but reduced in the M2 macrophages. On the contrary, mannose receptor (CD206) and macrophage galactose-type C-type lectin (CD301) were down-regulated on M1 macrophages but upregulated on the M2 macrophages in both mice and human M1 macrophages ^[75]. Among them, attention has been paid to Fc γ RI (commonly referred to as CD64), which is considered a suitable target molecule on M1 macrophages owing to their ability to bind and rapidly internalize monomeric IgG ^[76]. The development of antibodies against CD64, such as monoclonal antibody (mAb) 197, can specifically recognize and bind to monocytes, allowing for the development of macrophage-targeting technologies ^[77]. mAb 197 was used for the clinical treatment of chronic immune thrombocytopenia purpura (cITP), as mAb 197 binding prevented CD64 mediated destruction of IgG-coated platelets ^[78]. The murine-derived mAb 197 was further humanized (H22), which contained both binding specificity and high affinity for CD64, to reduce immunogenic response in human body ^[79]^[80].

TAMs, which are normally M2-like macrophages, facilitate tumor angiogenesis and growth, thus playing an indispensable role in tumor development and progression. Therefore, specific M2 TAMs have been considered as therapeutic targets in tumor treatment ^[81]. Recently, a M2 macrophage-binding peptide (M2pep) identified by phage display was reported to have high selectivity and efficient targeting ability to M2 macrophages ^[82]^[83]. Research has functioned gold NPs with M2pep to deliver siRNA in a lung cancer mouse model to achieve specific and long-lasting gene therapy in inflammatory TAMs ^[82]^[83]. Other cancer treatments, such as NPs-based magnetic hyperthermia therapy (MHT), were also performed. By coating iron oxide NP with M2pep in an orthotopic breast cancer mouse model, the M2 TAM-targeting MHT significantly reduced the tumor volume by reducing the population of pro-tumoral M2 TAMs in tumor ^[81]. Except for M2pep, another α-peptide (a scavenger receptor B type 1 targeting peptide), also possesses great specificity to M2-like TAMs ^[83]^[84]. Han et al. developed poly (lactic-co-glycolic acid) (PLGA) NPs conjugated both M2pep and α-pep to target M2 TAMs. This successfully transformed M2 to M1 phenotype, and remodeled the tumor microenvironment to allow the killing of tumor cells ^[85].

3. Application of Macrophage-Targeting Nanotechnology in Disease Treatment

3.1. Macrophage-Targeting NPs for Diagnosis

The role of NPs as an imaging/contrast agent enhancer in noninvasive diagnostic technique has been explored due to their unique physical and chemical properties. Moreover, the NP surfaces could be modified to improve the signal intensity and specificity, allowing them to be suitable for the diagnosis of different diseases. As macrophages are involved in the pathology of many diseases (e.g., infection, tumor, atherosclerosis, and rheumatoid arthritis), this cell type has been considered as a suitable imaging target. Monitoring the role of macrophages in inflammation can help researchers learn more about the pathological process of inflammatory diseases ^[39].

The superparamagnetic iron oxide (SPIO) NPs coated with macrophage-targeting agents, such as dextran ^[86]^[87]^[88], human ferritin protein cage ^[89], osteopontin (OPN) ^[90] or annexin V ^[91], can induce signal loss in T2-weighted images and, therefore, have been applied as MRI agent to offer pivotal insights into plaque biology, thus assessing inflammatory burdens in atherosclerosis. Lipinski et al. described a scavenger receptor-targeted micelle-based nanoparticle-containing MRI contrast agent for imaging macrophages in atherosclerosis. They reported that the NP could especially target and accumulate in macrophages, which significantly increased the contrast-to-noise ratio (CNR) by 52.5%, while the untargeted NP only increased CNR by 18.7% ^[35]. Likewise, Li developed class AI scavenger receptor-targeting, glutathione-biomineralized gadolinium-based NPs for noninvasive precise MRI imaging to detect foam macrophages in atherosclerosis plaque. The imaging contrast showed an amplified T1 signal, which precisely targeted macrophages, and exhibited systematic clearance capabilities ^[92].

In addition to MRI, CT imaging, which has high spatial resolution and short acquisition time, is another frequently used technology for diagnosis. However, the low sensitivity of CT requires the administration of a high dose of NPs, which needs to be investigated in future research. For example, iodine-containing NPs have shown advantages in identifying pro-inflammatory macrophages in vulnerable plaques, but the dose of iodine-NP is 100 mg/kg for mice ^[93], and the potential toxicity needs to be further studied. PET, which has high tissue penetration and superior sensitivity, is another non-invasive imaging technique. Keliher et al. introduced dextran-coated iron oxide NPs labeled with ⁸⁹Zr as macrophage-specific PET imaging agents due to their high affinity with macrophages ^[10]. Their later study described a PET radioactive tracer (¹⁸F)-labeled polyglucose NPs, which can be taken up by macrophages with high efficiency to visualize atherosclerotic plaques. This polyglucose NPs showed facilitated imaging in mouse and rabbit atherosclerosis models ^[94].

3.2. Macrophage-Targeting NPs for Tumor Treatment

As mentioned in this entry, TAMs contribute to tumor development via degradation of tumor extracellular matrix, destruction of the basement membrane, promotion of angiogenesis, and recruitment of immunosuppressive cells ^[85]. Therefore, TAMs have been proposed as therapeutic targets. Strategies have been made to clear TAMs in the tumor environment. Miselis et al. used clodronate-containing liposomes labeled with fluorescent dye to selectively target macrophages in the tumor spheroids and eliminate these cells from the tumor environment. In the animal tumor model, the treatment resulted in a 4-fold decrease in tumor number and a 15-fold decrease in tumor size compared to the control, suggesting that the liposomes successfully decreased the tumor cell density and enhanced apoptosis of tumor cells ^[95]. Soto et al. used mesoporous silica NPs (MSNs) to load Dox as chemotherapeutics and resulted in enhanced tumor growth arrest. The macrophage-targeting was achieved by encapsulating MSN-Dox into GPs derived from the cell walls of Baker’s yeast. The outer shells of GPs express β-glucan receptors (1,3-D-glucan polysaccharide) that allow for receptor-mediated selective uptake by macrophages ^[50]. Likewise, Ren encapsuled polymer−lipid hybrid NPs into GPs for macrophage-targeting delivery of cabazitaxel, which showed a slower in vitro drug release and higher drug stability compared with non-coated NPs ^[49].

The M2-like TAMs can be reprogrammed to M1-like macrophages to induce tumor cell necrosis by secreting inflammatory cytokines. Therefore, another strategy in tumor treatment is to induce the M2-to-M1 TAM phenotype switch to remodel the tumor microenvironment ^[85]. According to previous studies, TLR agonists (e.g., CpG oligodeoxynucleotides (CpG ODNs), which can induce anti-tumor M1 polarization) and baicalin (which can increase the production of IFN-γ) were used as immune modulators for cancer treatment ^[96]. However, due to the lack of effective delivery approaches, their applications in vivo are limited, suggesting the potential of M2-targeting NPs in delivery of TLR agonists. In Han’s research, PLGA NPs conjugated M2pep and α-pep peptides were used to transform the M2-like TAMs into the M1-like phenotype by specifically delivering a combination of CpG ODN and baicalin. The result showed that the NPs were effectively ingested by M2-like TAMs both in vitro and in vivo, and the released biomolecules effectively reversed the macrophage phenotype ^[85]. Shan et al. also developed human ferritin heavy chain (rHF) nanocages modified with M2pep on their surfaces for the targeted delivery of CpG ODNs to M2-like TAMs. These NPs were found to inhibit tumor growth in tumor-bearing mice after intravenous injection by transforming M2 TAMs to the anti-tumor M1 type. Moreover, they discovered that the empty M2pep-rHF NPs without CpG ODNs also exhibited anti-tumor ability ^[97]. Opanasopit et al. ^[98] introduced a mannosylated liposome containing an immunomodulator called muramyl dipeptide (MDP), which is a component derived from bacterial cell wall, to target macrophages and activate the M1 polarization in an experimental liver metastases animal model. The result showed that after stimulated by MDP, the production of prostaglandins, collagenase and super-oxide anions by macrophages increased significantly, which induced cytolytic activity against tumor cells ^[99].

Despite immunomodulation, TAMs are also therapeutic targets for anti-angiogenic treatment. TAMs secret MMPs to release matrix-sequestered VEGF and produce dozens of angiogenic factors to facilitate endothelial survival and proliferation, thus promoting angiogenesis, as well as tumor growth ^[100]^[101]^[102]^[103]. Penn invented dendrimer NPs conjugated with methotrexate (G5-MTX NPs), a chemotherapeutic that can be recognized by highly expressed FOLR2 on the surface of ovarian TAMs, for anti-angiogenic therapy. G5-MTX NPs overcame the resistance to anti-angiogenic therapy and prevented the side-effects of anti-angiogenic therapy (which induced the generation of cancer stem-like cells) and depleted TAMs in both solid tumor and ascites models of ovarian cancer ^[65].

Hyperthermia therapy has attracted increasing attention for tumor treatment, as tumor tissues are particularly vulnerable to hyperthermia compared with normal tissues owing to their faster cell proliferation, enhanced hypoxia, low pH, and insufficient temperature regulation ability ^[104]^[105]. Chen et al. developed HA conjugated gold nanorods with Dox and acid-labile hydrazone linker attached to the surface as photothermal NPs. After near infrared (NIR) laser irradiation, they enhanced drug release and increased drug toxicity on tumor cells owing to the photothermal effect ^[38]. Similarly, Wang developed a M2 TAM-targeting iron oxide nanoparticle for MRI-guided MHT of breast tumors. MHT can penetrate deeply into tissues to treat deep tumors and magnetic NPs are commonly used hyperthermia agents. Wang’s NPs also served as contrast agents for MRI, providing diagnostic information and visualizing their distribution in vivo to guide the optimal therapeutic time window ^[81].

Radiation-induced fibrosis (RIF) is a dose-limiting complication of cancer radiotherapy and causes serious problems, such as restricted tissue flexibility, pain, ulceration, or necrosis ^[106]. The recruitment of macrophages in inflamed sites can promote inflammatory events and result in fibrosis. Therefore, macrophages are potential cellular targets for anti-inflammatory treatment by inhibiting their production of cytokines. A study successfully treated RIF in a mouse model by intraperitoneal administration of chitosan NPs carrying siRNA to silence TNF-α in local macrophage populations, which takes advantage of the natural homing potential of macrophages to inflammatory sites. They observed the uptake of fluorescently labeled siRNA NPs by peritoneal macrophages and their subsequent migration to lesion region in radiation-induced inflammatory skin, suggesting the chitosan-siRNA NPs may serve as a general therapeutic approach for inflammatory diseases ^[106].

3.3. Macrophage-Targeting NPs for Infection Control

Infectious diseases are an important health concern, as several pathogens have adapted to survive inside the phagocytic cells, especially macrophages. In some cases, macrophages even serve as nutrient reservoirs to facilitate pathogen growth and spread. Therefore, new therapeutic strategies should be developed to allow for macrophage-targeting drug delivery ^[24].

Mycobacterium tuberculosis (Mtb) is one of the most threatening pathogens for its latent infection in macrophages. The intracellular Mtb isolated itself from drugs and could spread via macrophages ^[34]. Mtb displays lipoarabinomannan (LAM) on their cell wall. LAM contains mannose oligosaccharides at the terminus of the molecule, which dominate the attachment of bacteria to macrophages ^[107]^[108]^[109]. Therefore, mannosylated carriers can specifically target and competitively bind to macrophages to deliver antitubercular drugs. A mannose-modified macrophage-targeting solid lipid NP has been developed to load the pH-sensitive prodrug of isoniazid (INH) to treat the latent tuberculosis infection, and the modified NPs showed a higher cell uptake in macrophages (97.2%) than unmodified ones (42.4%), thereby increasing intracellular antibiotic efficiency ^[34]. Other studies also reported mannosylated gelatin microspheres, gelatin NPs ^[110], and solid lipid NPs ^[111]^[112]^[113] to carry anti-tuberculosis drugs (such as INH and rifampicin) to target alveolar macrophages. In all cases, increased macrophage uptake and higher reduction in bacterial levels were observed compared with non-mannosylated particles, maintaining therapeutic concentrations for a prolonged period even upon the administration of a reduced clinical dose ^[32]^[110]^[114]. Despite of the mannose, Sharma et al. explored wheat germ agglutinin coated poly (lactide-co-glycolide) NPs as nanocarriers of rifampicin, INH, and pyrazinamide to treat tuberculosis. This nanosystem could reduce the frequency of antitubercular drug administration, therefore improving patient compliance with tuberculosis chemotherapy ^[115].

Leishmaniasis is a common tropical infectious disease characterized by fever, anemia, weight loss, and the enlargement of the spleen and liver ^[66]. The etiological agents of leishmaniasis are protozoan parasites called Leishmania donovani, which are intracellular parasites targeting mononuclear phagocytes (monocytes and macrophages) and replicating within membrane-bound subcellular organelles. The parasites develop several mechanisms to survive in macrophages and inhibit parasite-specific cell-mediated host immune response ^[116]. The classical treatment of leishmaniasis is not effective due to drug resistance, toxicity, bioavailability, and cost ^[117]. Current treatment for leishmaniasis mainly depends on amphotericin B (AmB), which also has limitations, such as dose-related hematologic toxicity ^[118], naphrotoxicity ^[119], stability, and high cost. Therefore, targeted intracellular delivery of AmB is required to enhance drug efficiency and facilitate pathogen clearance. As mentioned previously, mannose-based carriers can specifically target macrophages via interaction with mannose receptors on the cell surface, so studies have developed mannose-anchored thiolated chitosan AmB nanocarrier complexes (MTC AmB) for clearance of Leishmania in macrophages. The result showed a 71-fold increase in MTC AmB uptake compared with native drugs and a 13-fold enhancement in drug efficacy ^[120]. Despite the mannose, Singh used PhoS, which can be recognized by scavenger receptors (such as CD68 and CD14) on macrophage surfaces for macrophage-targeting. They fabricated PhoS anchored PLGA NPs to deliver AmB, and found that those NPs preferentially accumulated in macrophage-rich organs, which significantly increased anti-leishmanial activity and continually released the drug within 72 h ^[66].

Human immunodeficiency virus (HIV) infects approximately 35 million people globally and results in 1.8 million deaths every year ^[121]^[122]. HIV mainly targets and survives in macrophages, assembling and accumulating in intracellular compartments in macrophages, thus escaping from immune clearance ^[123]. Given that inhibition of HIV replication could enhance the host response and control infections, studies have been performed to develop macrophage-targeting nanosystems to deliver anti-HIV drugs ^[124]^[125]. Zhou et al. decorated NPs with folic acid (FA), which can target folate receptor-β expressed on the surface of activated macrophages ^[126]. Long-acting cabotegravir, which is an antiretroviral drug, was encapsulated in the nanoparticle and specifically delivered into macrophages. The result showed the slow release of drugs from macrophages, allowing for sustained intracellular drug levels, thus facilitating long-term viral suppression ^[126].

Among individuals infected by HIV, approximately one-third of them are co-infected with Mtb. HIV-1 infection causes severe damage to the immune system, which enables Mtb to infect and survive in the body more easily. Meanwhile, Mtb infection increases HIV-1 replication, thus enhancing the severity of HIV infection. Given that both HIV-1 virus and Mtb mainly reside in mononuclear macrophages, Narayanasamy and colleagues introduced macrophage-targeting long-acting gallium (Ga) nanoformulation for drug delivery. As a crucial element for the metabolism and growth of most microorganisms, including Mtb and HIV, Ga could stay inside the macrophages for a long time, exhibiting long-term antivirus effects ^[127].

S. aureus is a Gram-positive bacterium that predominantly infects the skin and the respiratory system, and how to treat S. aureus infection in deep tissue remains a major challenge. Local infection can process into the most serious systemic S. aureus infection-sepsis ^[128]. The current approach to treat S. aureus infection is using small molecule antibiotics, which cause side effects, such as toxicity and drug resistance ^[129]. Due to their crucial function in immune response, macrophages are potential targets for anti-infection. Kim synthesized porous Si NPs carrying siRNA against Irf5 to promote phagocytosis of macrophages and inhibit their inflammatory function ^[130]. The porous Si NPs contain an outer sheath of homing peptides and fusogenic liposomes, allowing them to selectively target macrophages. Irf5 gene highly exists in M1 macrophages, upregulating inflammatory factors while downregulating anti-inflammatory cytokines ^[131]^[132]. Knockdown of Irf5 in the early stages of staphylococcal pneumonia can prevent the excretion of inflammatory cytokines and reverse prolonged inflammation, allowing the immune system to clear bacteria and repair tissue ^[133]^[134].

Nanotechnology has also been applied to develop novel vaccines against pathogens capable of inducing robust and protective autoimmunity. Chavez-Santoscoy et al. decorated the surface of polyanhydride NPs with specific carbohydrates to provide pathogen-like properties. The carbohydrates, galactose and di-mannose, which were found on the surface of respiratory pathogens, can facilitate both macrophage-targeting and immune activation ^[135]^[136]^[137]^[138]. This nanovaccine can promote robust pulmonary immunity against many respiratory pathogens, including Yersinia pestis, Mtb, Streptococcus pneumoniae and influenza viruses ^[41]. To develop an effective vaccine against HIV infection, a macrophage-targeting HIV immunotherapeutic vaccine based on NPs was introduced. The Ebola virus envelope glycoprotein was incorporated with non-replicating virus-like particles (VLPs) to enhance the NP’s macrophage and dendritic cells targeting capability, resulting in a stronger HIV-specific humoral immune response ^[139]. Hattori et al. introduced mannosylated liposomes, as DNA vaccine carriers and revealed enhanced Th1 immune response, suggesting that nanotechnology was a potent method for DNA vaccine therapy ^[39].

3.4. Macrophage-Targeting NPs for Bone Regeneration

Bone defects caused by diseases, such as trauma, tumor, and infection, often lead to the non-union of bones, delayed healing or non-healing, and local dysfunction. Although autologous bone transplantation has been widely used to cure bone defects, it has several disadvantages, such as the limited availability of graft volume, the morbidity of the donor site, and the prolonged operation time ^[140]^[141]^[142]^[143]. To solve these problems, synthesized biomaterials incorporated with osteoinductive factors have become a promising way to treat bone defects ^[140]^[141]^[142]^[143]. Recent studies have found that the immune system is closely associated with the skeletal system by regulating the biological behavior of bone cells ^[144]^[145]^[146]^[147], especially for biomaterial applications. Once a foreign material enters the body, it is immediately recognized by the immune system. It triggers activation/inflammation of the immune system, which then influences the subsequent bone regeneration and eventually determines the success of bone biomaterial application in vivo ^[146]^[147]. The relationship between foreign biomaterials, host immune cells, and bone cells, is termed as “osteoimmunomodulation”, and biomaterials with appropriate osteoimmunomodulatory capacity can, therefore, modulate local immune microenvironment to favor osteogenesis ^[148]^[149].

Among immune cells, the macrophage is one of the most important cell types. The upregulated release of proinflammatory cytokines, including IL-1β, IL-6, and TNF-α from M1 macrophages results in suppression of osteogenesis ^[150]^[151] and increased osteoclastogenesis ^[152]. On the contrary, the anti-inflammatory M2 phenotype can release osteogenic cytokines, such as BMP2 and VEGF, to eliminate inflammation and promote bone healing ^[153]^[154]^[155]. Therefore, nanomaterials are emerging as effective agents able to target macrophages, inducing their M2 polarization and thus modulating bone regeneration. One way to stimulate M2 polarization is to change the surface chemistry of NPs by using bioactive molecules, such as conjugating gold NPs with RGD ^[156], hexapeptides Cys-Leu-Pro-Phe-Phe-Asp ^[152], and IL-4 ^[157], or coating hydroxyapatite on the surface of CeO₂ NPs ^[158]. It is noteworthy that some NPs themselves can enhance M2 polarization, such as gold, TiO₂, and CeO₂ NPs ^[159]^[160]^[161]. In addition, the nanopore structure and pore size were found to affect the spreading and cell shape of macrophages by modulating their adhesion, which subsequently influences their autophagy, inflammatory response, and release of osteogenic factors ^[162]^[163]. For example, Chen found that macrophages on surfaces with larger sized pores (100 and 200 nm) become more anti-inflammatory, producing more pro-inflammatory cytokines and increasing the production of M2 surface-markers ^[162]. Surface roughness of biomaterials also influences macrophage polarization and cytokine secretion. Studies indicated that titanium with the smooth surface could stimulate M1 macrophage activation, expressing inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, while rough and hydrophilic titanium surface enhanced anti-inflammatory macrophage polarization with the increased secretion of IL-4 and IL-10 ^[164].

Using nanosystems as carriers to deliver bioactive molecules (including growth factors, cytokines, gene-modulators, and signaling pathway regulators) is another way to induce M1-to-M2 polarization of macrophages. For example, exogenous addition of sphingosine-1-phosphate (S1P), which is a sphingolipid growth factor, stimulates macrophages toward M2-like phenotype ^[165]. In the study by Das et al., fused nanofibers loaded with S1P synthetic analog were used to direct macrophage polarization towards M2-like phenotype in a mandibular bone defect model and successfully facilitated the osseous repair ^[166]. Yin et al. developed gold nanocages (AuNC) coated with LPS-stimulated macrophages cell membranes to deliver an anti-inflammatory drug named esolving D1. After LPS stimulation, cytokine receptors on the cell membrane were overexpressed and were able to neutralize pro-inflammatory cytokines ^[167]. This nanosystem was found to effectively reverse inflammation, facilitate M2 activation and promote osteogenesis in the femoral defect. IL-4 is a well-known anti-inflammatory cytokine, so various nanocarriers have been developed to load IL-4 to induce M2 polarization ^[168]^[169]^[170]. A nanofibrous heparin-modified gelatin microsphere incorporated with IL-4 was developed to resolve the chronic inflammation caused by diabetes and enhance osteogenesis ^[169]. In another study, the gene of CD163 (a M2 macrophage marker belonging to the scavenger receptor cysteine-rich family) was encapsulated into polyethyleneimine NPs decorated with a mannose ligand to selectively target macrophages to transfer them into anti-inflammatory phenotype ^[171].

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