Nanoparticles-Based Platforms Targeting the PD-1/PD-L1 Pathway: History
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Contributor:
Xin Yu
,
Chao Fang
,
Kun Zhang
,
Chunxia Su

Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis showed remarkable improvements in overall response and patient survival, which changed the treatment landscape for multiple cancer types. PD-1/PD-L1-targeted agents encapsulated in nanoparticles have emerged as novel drug delivery systems for improving the delivery efficacy, enhancing immune response and minimizing side effects in cancer treatment. Nanocarriers targeting the PD-1/PD-L1 axis showed enhanced functionalities and improved technical weaknesses based on their reduced off-target effects, biocompatible properties, multifunctional potential and biomimetic modifications. 

  • PD-1/PD-L1
  • immune checkpoint
  • nanoparticles
  • delivery nanoplatforms

1. Introduction

A variety of treatments have been developed for different malignancies, including surgery, radiotherapy, chemotherapy, immunotherapy, and others. In recent years, cancer immunotherapy has represented a turning point with the widespread use of immune checkpoint inhibitors (ICIs). Unlike other therapies, immunotherapy aims to boost the immune system and eliminate tumors, ultimately aiding in treating cancers, reducing metastasis, and preventing recurrence. There are a number of checkpoints that have been discovered and targeted, including PD-1/PD-L1, CTLA-4, LAG-3, TIM-3, TIGIT, and so on [1]. Among them, the PD-1/PD-L1 pathway appears to be the most effective and successful target in the drug development pipelines. ICIs targeting PD-1 and PD-L1 have provided durable clinical responses and long-term survival in a subset of patients. However, the majority of patients administered with PD-1/PD-L1 antibodies are either non-responders or eventually develop acquired resistance [2]. Thus, several techniques have been introduced in clinical practice to improve the efficacy of immunotherapy, including the combination of immunotherapy with chemotherapy, radiotherapy, antiangiogenic therapy, and other immunomodulatory drugs [3]. These approaches are designed to impinge on different components of tumor biology to achieve additive or synergistic antitumor activities. However, another concern are more serious side effects in the context of combination therapy.

2. Nanoparticles Directly Targeting the PD-1/PD-L1 Pathway

2.1. Nanoparticles Delivering Antibodies and Peptides

Despite the outstanding therapeutic effect of PD-1/PD-L1 antibodies, limitations still exist, such as the non-specific delivery of drugs and their limited intratumoral accumulation levels. NP-based ICI therapies could enhance the tumor-specific immune responses and reduce the irAEs to increase the safety profiles. Lim et al. prepared the phenylboronic acid–antibody (pPBA-Ab) nanocomplex by the simple mixing of polymeric phenylboronic acid (pPBA) and anti-PD-L1 antibodies at the desired ratio [4]. The phenylboronic ester was formed by the phenylboronic acid and the diol moiety of the glycosylation site of the antibody. This nanoparticle had an elongated circulation owing to the protective polymer shell and could accumulate in tumor sites by the EPR effect. Additionally, the dissociation of phenylboronic ester and the release of loaded cargo were accelerated in the acidic tumor microenvironments. In vivo studies demonstrated that this nanocomplex showed superior antitumor effects than free antibodies in MC-38 tumor-bearing mouse models. Moreover, Bu et al. created dendrimer–ICI conjugates (G7-αPD-L1) to increase the binding avidity of ICI antibodies by the multivalent binding effect [5]. This system showed enhanced binding strengths to PD-L1 molecules compared with free αPD-L1, which could translate into the efficiency and antitumor effects both in vitro and in vivo. The efficacy of ICIs was unsatisfactory in intracranial tumors in part because of the insufficient drug penetration across the blood-brain barrier (BBB). As a benzamide analogue, p-hydroxybenzoic acid (pHA) displayed great capabilities to cross the BBB. 
Ferritin-based nanocages with multiple loadings could awaken the host immune system and provoke a strong and durable response in cancer treatment, which are attractive as nanocarriers [6]. A study developed PD-1-decorated nanocages (PdNCs) by surface engineering, which could remarkably increase the binding affinity of the ligands and provide enhanced antagonistic efficiency. With a desirable nanocage size of about 20 nm, PdNCs could rapidly be drained and accumulated into the tumor-draining lymph nodes (TDLNs). In vivo studies showed that the PdNCs treatment induced the maturation of the DC and the tumor-specific T cell responses both in TDLNs and TMEs. These behaviors can inhibit tumor growth and induce tumor eradication in some tumor-bearing mice [7]. 5-Aza-20-deoxycytidine (DAC) functions as an epigenetic agent to block de novo DNA methylation in activated PD-1+CD8+ TILs and can help to boost antitumor immunity in immunotherapy. 

2.2. Nanoparticles Delivering RNA

RNA interference (RNAi) is a conserved cellular pathway of post-transcriptional gene regulation, which includes endogenous microRNA (miRNA) and short double-stranded RNAs called small interfering RNA (siRNA). siRNA can be designed to knock down any genes, which expands the druggable targets of the human genome extremely. For cancer treatment, siRNA could be used to inhibit the expression of genes related to cell survival, proliferation, and cell cycle progression, providing an encouraging opportunity for drug design [8]. Thus, it is possible to use siRNA for targeting PD-L1 and reduce the de novo expression of PD-L1 proteins in cancer cells. However, naked siRNA is prone to degradation, too large, and too negatively charged to pass through the cell membrane. In order to implement it in clinical practice, effective and safe delivery systems have to be developed [9].
Kwak et al. designed a complex to deliver siRNA with a polymeric carrier (“pd”) consisting of disulfide-cross-linked polyethylenimine (CLPEI) and dermatan sulfate (DS). This siRNA/pd reduced the expression of PD-L1 and attenuated the expression of cancer-related genes in B16F10 cells. Both C57BL/6 mice and immune-compromised nude mice models showed tumor growth suppression. They also observed a strong correlation between PD-L1 and p-S6k, a marker of mTOR pathway activation in tumors, indicating siRNA/pd could act on both immune checkpoint and the tumorigenesis signaling pathway [10]. In addition, further research is intended to deliver the PD-L1 siRNA by folic acid (FA)–functionalized polyethylenimine (PEI) polymers. These complexes increased the uptake of siRNA into SKOV-3 epithelial ovarian cancer cells, which express folate receptors and decreased monocyte uptake, resulting in about 40–50% PD-L1 protein knockout. Notably, compared with siRNA controls, SKOV-3 cells treated with (PEG)-FA/PD-L1 siRNA were twice more sensitive to T cell killing [11]. These results highlight the modified PEI for potentially being used as gene carriers.
One of the key technological problems for delivering siRNA into cells is overcoming the lipid bilayer, which means escaping from the endosome and reaching the cytoplasm to silence gene expression [12]. In order to achieve efficient endosome escape, Li et al. formed a pH-sensitive copolymer siRNA-loaded PDDT nanomicelles (PDDT-Ms/siRNA) and investigated in vitro and in vivo performance [13].

3. Nanoparticles for Combining PD-1/PD-L1 Blocking and Other Therapies

3.1. Nanoparticles Combining PD-1/PD-L1 Blocking and Chemotherapy

A rational combination of immunotherapy and chemotherapy can influence different elements of tumor biology to achieve additive or synergistic antitumor effects. The two main ways in which chemotherapy promotes tumor immunity are by inducing immunogenic cell death as part of its intended therapeutic effect, and by disrupting strategies used by tumors to evade immune recognition [14][15]. Although this combination regimen had shown superior to chemotherapy or immunotherapy alone in many cancer types, management of treatment-related adverse events was always a tough question. Thus, it is essential to develop novel delivery systems to achieve the co-delivery of the two categories of drugs. Duan et al. developed a self-assembled core-shell nanoparticle (OxPt/DHA) in which the nano coordination polymers of Zn and OxPt prodrugs were coated in lipid bilayers containing cholesterol-DHA conjugate (chol-DHA). OxPt and DHA had strong synergic effects in generating reactive oxygen species (ROS) and anticancer functions. Furthermore, the addition of anti-PD-1 antibodies with OxPt/DHA therapy could awaken innate and adaptive immune responses and eradicate tumors of murine colorectal cancer [16]. Kinoh et al. applied pH-sensitive epirubicin-loaded micellar nanomedicines to synergy with anti-PD-1 antibodies against both PTEN-positive and PTEN-negative orthotopic glioblastoma. The combination therapy could transform the cold TME into a hot condition with the high infiltration of anticancer immune cells and the eradication of immune suppressive cells [17]. A combination of leucovorin (LV) and fluorouracil (FU) with oxaliplatin (FOLFOX) has been known as the standard first-line therapy for advanced colorectal cancer for decades [18]. In order to improve the clinical benefits of the FOLFOX regimen, Guo et al. formed a nanoparticle using the active form of oxaliplatin and folinic acid, which were encapsulated into an aminoethyl anisamide-targeted PEGylated lipid NPs [19]. As a result, Nano-Folox achieved stronger chemo-immunotherapeutic responses compared to FOLFOX. Anti-PD-L1 antibodies further enhanced the efficacy of Nano-Folox in reducing liver metastases in an orthotopic CRC mouse model.
Recent research showed that miR200C could inhibit PD-L1 expression and improve the susceptibility of cancer cells to chemotherapy agents. Phung et al. constructed dual drug-loaded nanoparticles delivering doxorubicin (DOX) and miR-200c (DOX/miR-NPs) [20]. Folic acid-modified NPs increased the uptake by tumor cells in vitro and the accumulation in the TME in vivo. Notably, DOX/miR-NPs significantly inhibited PD-L1 expression and induced immunogenic cell death both in vitro and in vivo. These results revealed that miR200c could facilitate the efficacy of chemotherapy drugs in cancer treatment. Peptide drugs targeting the PD-1/PD-L1 pathway have emerged as a promising therapy for cancer. Phosphatidylinositol 3-kinase (PI3K) is known to influence the balance between M1/M2 macrophage polarization to regulate the immune response. Song et al. designed an albumin NP (Nano-PI) encapsulating paclitaxel (PTX) and the PI3K inhibitor (IPI-549) [21]. The combination of anti-PD-1 with Nano-PI remodeled the TME in two breast cancer mice models and induced long-term tumor remission. Mechanically, PTX combined with IPI-59 enhanced the M1 repolarization, increased immune-effector cells and decreased immune-suppressive cells, while Nano-PI facilitated the delivery of the two drugs to lymph nodes and tumor sites. This strategy represented a potential candidate for clinical practice. Li et al. developed a self-assembled nanovehicle (SNV) from the immunogenic cell death-inducing copolymer and PD-L1 blocking copolymer to elicit mitochondrial-targeted immunogenic cell death induction and PD-L1 blocking [22]. It has the properties of long-circulating, better accumulation into tumors and mitochondrial targeting. In vivo studies demonstrated the remarkably immune response and antitumor activity in both B16F10 and 4T1 tumors.
Membrane nanovesicles (NVs) had advantages in delivering drugs, such as high flexibility, ease for surface manipulation, and great biocompatibility and biodegradability. Using genetic engineering methods, antibodies could be linked to the exterior of cell-membrane-derived nanovesicles. The antibodies maintained their biological activity and efficiently delivered drugs to specific tumor cells [23]. Li et al. prepared cluster of differentiation 64 (CD64) as fragment crystalline (Fc) catchers and to be overexpressed in membrane NVs for PD-L1 antibody delivering (CD64-NVs-aPD-L1) [24]. Meanwhile, the chemotherapy agent cyclophosphamide (CP) was loaded into this NP to enhance antitumor effects by unleashing the effect of CD8+ T cells and restraining Tregs activity. In the mouse melanoma model, CD64-NVs-aPD-L1 could intensively suppress the tumor growth and improved the survival time without obvious changes in body weight. In summary, membrane-derived NVs could achieve both checkpoint blockades and chemotherapy for combined cancer immunotherapy.

3.2. Nanoparticles Combining PD-1/PD-L1 Blocking and Radiotherapy

As a hallmark of GBM, tumor-associated myeloid cells (TAMCs) are key factors of immunosuppression in the TME and could account for up to 50% of the tumor mass, which impedes the efficacy of immunotherapy or other traditional therapies. As PD-L1 molecules are highly expressed on glioma-associated TAMCs, Zhang et al. designed and reported a lipid nanoparticle (LNP) decorated with anti-PD-L1 antibodies on its surface [25]. This platform (αPD-L1-LNP) was further encapsulated with a cyclin-dependent kinase (CDK) inhibitor dinaciclib to induce the depletion of TAMCs and impair their immunosuppressive roles. Notably, the targeting efficiency of αPD-L1-LNP/Dina was strengthened with additional radiotherapy (RT) due to the RT-induced PD-L1 upregulation on TAMCs. Combining RT with αPD-L1-LNP/Dina resulted in the prolonged survival of two syngeneic glioma mice models of CT2A and GL261. This phenomenon was also validated towards human TAMCs from GBM patients. Thus, this research explored a potential approach to improve the clinical outcomes of patients with GBM and needed to be further verified. In another study, Erel-Akbaba et al. designed a solid lipid nanoparticle (SLN) conjugating with a cyclic peptide iRGD to deliver siRNAs against PD-L1 and EGFR for GBM [26]. They found that low-dose radiation facilitated SLN to locate in the tumor site, leading to the down-regulation of PD-L1 and EGFR expression. RT followed by the administration of SLN resulted in a decrease in tumor growth based on bioluminescence imaging. Overall, this work illustrated an approach for using RT to increase NPs uptake and effectively target the EGFR and PD-L1 pathways in GBM, which could be probably extended to other malignancies.
Confirmation and intensity-modulated RT have been extensively investigated in the past few decades. Radiation enhancers can not only decrease the dose of X-rays but also precisely target the tumor cells to reduce side effects [27]. Ni et al. developed two porous Hf-based metal-organic frameworks (nMOFs), Hf6-DBA and Hf12-DBA nMOFs, that significantly outperformed HfO2 to enhance the effects of the X-ray RT [28]. The combination of nMOF-mediated RT with PD-L1 blockade effectively eliminated the primary tumor and distant tumor via abscopal effects. The advantages of nMOFs included tumor-targeting properties to minimize the irradiation dose and maintain sufficient ionizing damage to the tumor cells. This work proved the feasibility of using nMOFs as an assisted therapy for immunotherapy.

3.3. Nanoparticles Combining PD-1/PD-L1 Blocking and Other Immune Checkpoint Blockers

At present, there are many other immune checkpoints been discovered and served as drug targets, such as CTLA-4, TIM-3, LAG-3, TIGIT, VISTA, etc. As some drugs enter clinical trials and daily practice, PD-1/PD-L1 inhibitors combined with other checkpoint blockers have shown significant immune response and tumor shrinkage. In order to achieve better synergistic effects, nanoparticles for the combination of immunotherapy approaches are urged to be investigated. A self-degradable microneedle (MN) patch composed of hyaluronic acid and dextran nanoparticles that loaded anti-PD-1 and glucose oxidase was developed [29]. In vivo study revealed that the efficacy of the MN patch in inhibiting tumor growth was better than the intratumoral injection of free anti-PD-1. In addition, the combination of anti-CTLA4 and anti-PD-1 antibodies’ co-delivery by MNs showed a remarkable synergistic effect in comparison to either acting individually in the B16F10 melanoma mice model. Of mice receiving the combination regimen, 70% achieved complete control of the tumor and reached disease-free survival in 60 days. Galstyan et al. developed targeted nanoscale immunoconjugates (NICs) using a versatile drug carrier poly (β-L-malic acid) (PMLA) and covalently attached with αPD-L1 and αCTLA-4 for systemic delivery across the blood-brain barrier and glioma therapy [30]. The distribution of drugs in tumor sites was examined using two vascular labeling methods and tumor parenchyma showed significantly more NIC-attached antibodies than free antibodies. NICs treatment also leads to increased immune-activating cells in tumor areas and favorable prognoses in glioma-bearing mice. Notably, the NICs combination showed the highest survival of mice compared to single NICs or free antibodies, demonstrating the superior efficacy of dual checkpoint inhibition.
It is generally agreed that acidic pH is a major attribute of TME that enhances tumor immune evasion. Jin et al. found that an acidic pH environment could upregulate co-inhibitory checkpoint receptors like PD-1, TIM-3, LAG-3, and TIGIT, and inhibit Akt/mTOR activation in memory CD8+ T cells [31]. Additionally, extracellular tumor acidity increased the suppressive function of the TIGIT-CD155 axis. Therefore, they used Pluronic F-127 (a NaHCO3 releasing carrier) to alleviate the extracellular acidic pH environment. In vivo experiments showed that pH modulating injectable gel (pHe-MIG) transformed the immuno-suppressive TME to a favorable condition and the combination of pHe-MIG with PD-1 and TIGIT inhibitors boosted the immune response and synergistically improved the antitumor effects, which could be a novel method for designing immunotherapies. Huang et al. designed a liposome-based photothermal therapy (PTT) nanoparticle through the self-assembling injectable lipids and photothermal agent indocyanine green (ICG) [32]. The obtained nanoparticle could efficiently eradicate the tumor in CT26 and MC38 mice models. Moreover, the distant tumor growth correlated with the upregulation of immune checkpoints like PD-1 and TIM-3 after PTT therapy. Dual PD-1 and TIM-3 blockade combination generated a systemic response and significantly inhibited tumor growth both in primary and distant sites.

3.4. Nanoparticles Combining PD-1/PD-L1 Blocking and Photodynamic Therapy (PDT)

PDT is a non-invasive and modern form of therapy, which is based on the application of photosensitizers (PS). Mechanistically, PS molecules are activated by the light with an appropriate wavelength, aiming to destroy the target cells in the pathological tissues [33].
PDT could be divided into type I PDT and type II PDT based on their photochemical reaction processes, generally, type I PDT occurs in hypoxic environments and type II PDT dominates in oxygenated conditions [34]. With the development of nanotechnology, nanoparticles combined with photosensitizers can improve the efficiency and selectivity of photodynamic therapy and reduce adverse events as well. Here, researchers discuss the rationale for combining PD-1/PD-L1 blockades and PDT to expand the application for immunotherapy in cancer.
Feng et al. synthesized the acid-responsive polygalactose-co-polycinnamaldehyde polyprodrug (PGCA) for self-assembling into NPs that deliver PA (PGCA@PA NPs) [35]. ROS level was increased by the combination of cinnamaldehyde (CA) and photosensitizer pheophorbide A (PA) with light irradiation in cancer cells. Moreover, when combined with anti-PD-1 therapy, PGCA@PA NPs significantly promoted T cell infiltration and boost immune response in melanoma.
The efficacy of PDT in cancer treatment is usually limited because of its hypoxia resistance. Based on nanoscale metal-organic frameworks (nMOFs), Lan et al. designed Fe-TBP as a photosensitizer to sensitize PDT in hypoxic conditions [28]. Fe-TBP was composed of iron-oxo clusters and porphyrin ligands, which exhibited effective cellular uptakes. Meanwhile, Fe-TBP-mediated PDT could enhance the accumulation of cytotoxic T cells in TME. The combination of Fe-TBP and anti-PD-L1 treatment resulted in the >90% regression of tumors in the colorectal mouse model. Perfluorotributylamine (PFTBA) and sinoporphyrin sodium (DVDMS) were encapsulated into the nanovesicles. The perfluorocarbon could transport oxygen and serve as an oxygen source in a hypoxic environment [36]. The co-delivery of a PD-1 protein and a photosensitizer achieved a synergistic effect of photodynamic immunotherapy, which completely inhibited both primary and distant 4T1 tumors in vivo.

3.5. Nanoparticles Combining PD-1/PD-L1 Blocking and Photothermal Therapy (PTT)

PTT utilizes photothermal transduction agents (PTAs) that convert the energy into heat to trigger the thermal ablation of tumors. Compared with other therapies, PTT provides the advantages of the precise targeting of the tumors with adjustable laser irradiation, which avoids severe adjacent healthy tissue damage [37]. Although it is an effective and non-invasive method capable of treating tumors, local recurrence and metastasis would probably happen because of uneven heating and poor immune response. Immunotherapy could elicit a strong immune response to effectively treat a wild variety of cancers. Thus, combining PTT with immunotherapy to generate potential synergistic effects is of great interest to researchers.
Near-infrared (NIR) light-triggered inorganic materials are applied extensively, which show favorable absorbance abilities, great photothermal conversion properties, and excellent photo-stabilities [38]. Zhang et al. synthesized multifunctional NPs loading anti-PD1, perfluorobutane (PFP), and iron oxide (GOP@aPD1) [39]. In vivo, GOP@aPD1 NPs were intravenously injected into B16F10 melanoma-bearing mice, which achieved the synergistic antitumor efficacy mediated with PTT duo to the efficient delivery of anti-PD1 and increased CD8+ T cells accumulation in tumor sites. Of note, GOP@aPD1-PTT-treated mice showed desirable tumor regression compared with anti-PD1 immunotherapy. This research verifies the novel strategy of GOP@aPD1-based PTT, which provides the rationale for combining immunotherapy with photothermal treatment. Different from conventional PTT, which directly kills tumor cells, Huang et al. used mild PTT (MPTT) as a regulatory mechanism for tumor immunotherapy [40]. MPTT can alter the TME by activating the systemic immune response, increasing tumor T cell infiltration, and turning ‘cold’ tumors into ‘hot’ tumors, thereby enhancing the effect of anti-PD-L1 antibody on immune checkpoint blockade. Through the thermal effect of IR820 induced by NIR, the reversible phase transition of the packaging aPD-L1 lipogel (LG) was regulated to achieve the controlled release of aPD-L1 and increase the recruitment of TILs to boost T-cell activity in vivo.
Large-pore mesoporous silica nanoparticles (MSNs) are attracting more attention and interest because of their high biodegradability, large-pore structure, and easy-modified properties [41]. Zhang et al. designed a multifunctional nanoplatform for photoacoustic (PA) and ultrasound (US) photothermal combined immunotherapy [42]. The nanocomposites had a copper sulfide (CuS) core and mesoporous silica shell loading perfluoropentane (PFP) and possessed excellent biocompatibility, PA/US imaging, and strong PTT effect irradicated by 808 nm laser, which indicated a potential application of molecular classification, diagnosis, and treatment of breast cancer. More importantly, in vivo experiments showed that nanoplatform-mediated PTT combined with anti-PD-1 blockade was capable of obliterating primary tumors and inhibiting metastatic tumors. In another study, Chen et al. developed a resembled nanoplatform based on dendritic large-pore MSNs with the ability of photothermal and immune remodeling for treating triple-negative breast cancer (TNBC) [43]. The CuS nanoparticles with great photothermal conversion efficacy were in situ deposited in the pores of MSNs and resiquimod (R848) were encapsulated simultaneously as immune adjuvants. On the surfaces were homogenous cancer cell membranes decorated with anti-PD-1 peptide AUNP-12. The obtained AM@DLMSN@CuS/R848 exhibited high targeting ability and tumor ablation with 980 nm laser irradiation. The photothermal effect caused tumor antigens and R848 releasing, and AUNP-12 was also dissociated via the cleavage of the benzoic-imine bond in the weakly acidic TME, which synergistically boosted immune response and vaccine-like functions to prevent TNBC recurrence and metastasis. The two studies provide an insight into the intelligent nanoplatforms to ameliorate clinical outcomes in metastatic TNBC.

3.6. Multifunctional Nanoparticles Containing PD-1/PD-L1 Blocking

Tumor immunotherapy involves a continued multilink process including antigen presentation (Phase I) lymphocyte activation and proliferation/differentiation (Phase II), and tumor elimination (Phase III). Thus, the ideal platform is capable of simultaneously performing the three phases. Li et al. reported a three-in-one immunotherapy nanoplatform aPD-L1@HC/PM NPs containing anti-PD-L1 antibodies, chlorin e6 (Ce6)-conjugated hyaluronic acid (HC), and 1-mt-conjugated polylysine (PM) [44]. Immunogenic cell death induced by Ce6 under NIR irradiation promoted antigens releasing and initiated phase I antitumor response. The IDO inhibitor 1-mt and anti-PD-L1 antibody towards their own targets unleashed the immune-suppressive states to eliminate tumors, corresponding to the Phase II and III stages, respectively. Flow cytometry and microscopic photograph results both showed that aPD-L1@HC/PM NP plus irradiation could promote DC maturation, indicating its efficient role in PDT-induced antigen presentation for DC maturation (Phase I). In vitro studies also showed that the T cell proliferation index (PI) for the aPD-L1@HC/PM NP group was higher than that of the control group (45.6 vs. 2.66%). In addition, aPD-L1@HC/PM NP induced several cytokines, including IL-2, IFN-γ and TNF-α in Phase III. In melanoma-bearing mice models, the aPD-L1@HC/PM NPs were proven to be the most effective for abscopal tumors. Overall, this platform was valuable for boosting all-immunity-phase immunotherapy as a nanoweapon.

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics14081581

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