Immune-regulating camouflaged nanoplatforms: A promising strategy to improve cancer nano-immunotherapy

Abstract

Although nano-immunotherapy has advanced dramatically in recent times, there remain two significant hurdles related to immune systems in cancer treatment, such as (namely) inevitable immune elimination of nanoplatforms and severely immunosuppressive microenvironment with low immunogenicity, hampering the performance of nanomedicines. To address these issues, several immune-regulating camouflaged nanocomposites have emerged as prevailing strategies due to their unique characteristics and specific functionalities. In this review, we emphasize the composition, performances, and mechanisms of various immune-regulating camouflaged nanoplatforms, including polymer-coated, cell membrane-camouflaged, and exosome-based nanoplatforms to evade the immune clearance of nanoplatforms or upregulate the immune function against the tumor. Further, we discuss the applications of these immune-regulating camouflaged nanoplatforms in directly boosting cancer immunotherapy and some immunogenic cell death-inducing immunotherapeutic modalities, such as chemotherapy, photothermal therapy, and reactive oxygen species-mediated immunotherapies, highlighting the current progress and recent advancements. Finally, we conclude the article with interesting perspectives, suggesting future tendencies of these innovative camouflaged constructs towards their translation pipeline.

Keywords: Biological camouflage; Immune-regulating; Immunogenic cell death; Nanovaccine; Prolonged blood circulation.

Graphical abstract

Fig. 1

Schematic illustrating different types of immune-regulating camouflaged nanoplatforms with evading immune clearance or enhancing immune response functions to enhance the currently established immunotherapies and some ICD-inducing immunotherapies.

Fig. 2

(a) Schematic illustration of the redox-responsive sulfur dioxide‒releasing nanosystem with a prolonged circulation time for producing the synergistic effect of chemotherapy and gas therapy. (b) Fabrication of MON-DN@PCBMA-DOX and the structure of MON and PCBMA. (c) Mechanism of controlled drug release and combination therapy. Reproduced with permission from Ref. [45] Copyright 2020, John Wiley & Sons.

Fig. 3

Schematic illustrating the mechanism of antitumor immune responses induced by PLGA-R837@Cat-based radiotherapy combined with checkpoint-blockade to inhibit cancer metastases and recurrence. Reproduced with permission from Ref. [53] Copyright 2019, John Wiley & Sons.

Fig. 4

In vitro immune clearance evasion, pharmacokinetics, and biodistribution of MSN@M. (a) MSN@M could avoid phagocyte clearance through CD47 and target tumor sites through their homing ability. (b) RAW 264.7 cell uptake of MSN and MSN@M at different time points captured by CLSM, scale bar = 5 μm, and (c) flow cytometry analyzing of the fluorescence intensity of FITC-MSN@M and FITC-MSN in RAW 264.7 cells at 2 h and (d) 4 h (n = 3, *p < 0.05, **p < 0.01). (e) Blood retention of MSN@M, MSN, and free FITC (dosage of FITC at 1 mg/kg) in HepG2 xenograft mice after one dose intravenous injection to analyze the pharmacokinetics of MSN@M (n = 3, *p < 0.05, **p < 0.01, ***p < 0.001). (f) Distribution of ICG-MSN@M, ICG-MSN, and free ICG in HepG2 xenograft nude mice at 4, 8, 12, and 24 h after tail vein injection of 0.8 mg/mL ICG-MSN@M, ICG-MSN, and free ICG. The tumor size of HepG2 xenograft mice was approximately 150 mm³. (g) Distribution of ICG-MSN@M, ICG-MSN, and free ICG in tumor site of HepG2 xenograft nude mice at 24 h and (h) fluorescence quantitative analysis of signal intensity in tumor site of three groups at 24 h (n = 3, *p < 0.05, ***p < 0.001). (i) Ratio of the fluorescence signal at major organs and tumor site to the total fluorescence signal in the ICG-MSN@M, ICG-MSN, and free ICG groups at 24 h (n = 3, *p < 0.05, ***p < 0.001). (j) CLSM image of the distribution of MSN@M and MSN in tumors after tail vein injection of 1 mg/mL FITC-MSN@M, FITC-MSN, and free FITC. Left scale bar = 750 μm, right scale bar = 100 μm. Reproduced with permission from Ref. [81] Copyright 2020, Elsevier.

Fig. 5

(A) Schematic illustration of the tumor-associated-macrophage-membrane-coated upconversion nanoparticles for improved photodynamic immunotherapy. Reproduced with permission from Ref. [93] Copyright 2021, American Chemical Society. (B) Generation and characterization of DCNV-rAd-Ag. a) Generation of DCNVs derived from adenovirus-infected mature dendritic cells. (1) The genes of tumor-specific antigen were genetically engineered into the adenovirus vector. (2) Recombinant adenovirus infected the immature DC2.4 cells to express the modified antigen on the cell surface and stimulate it. (3) Differentiation, maturation, and antigen presentation. (4) Harvesting of the induced mature cell membrane and preparation of DCNV-rAd-Ag. b) Schematic illustration of the generation of DCNV-rAd-Ag. c,d) Cryo-electron microscopy (c) and dynamic light scattering analyses (d) showed uniform DCNV-rAd-Ag (approximately 108 nm average diameter, polydispersity index = 0.14) with a vesicle-like morphology. Scale bar, 50 nm. e) The Western blot on membrane proteins from DCNV-rAd-GFP demonstrates a similar protein content on the surface compared to that of the parental cells. Panels (c–e) show representative results of two independent experiments with similar results. f) Comparison of upregulated immune-response-related proteins in NVs and DCs. g) The relative abundance of antigen presentation and migration-related proteins on DCNV-rAd-GFP. r.p.m., revolutions per minute. CCR - CC chemokine receptor; CXCR - C-X-C chemokine receptor; EpCAM - epithelial cellular adhesion molecule; ICAM 1 - intercellular adhesion molecule 1; pMHC-I - peptide-major histocompatibility complex class I. Reproduced with permission from Ref. [98] Copyright 2022, Springer Nature.

Fig. 6

The design principle of hGLV and the antitumor mechanism of hGLV through PTT combined with immunotherapy. Abbreviation: exos, exosomes; TSL, thermosensitive liposomes; hGLV, gene-engineered exosomes-thermosensitive liposomes hybrid nanovesicles; DCs, dendritic cells. Reproduced with permission from Ref. [109] Copyright 2021, Elsevier.

Fig. 7

(A) Schematic of Mn²⁺-induced M1 macrophages polarization and the synergistic anticancer effect of M1 Exo-engineered with aCD47 and aSIRPα. Reproduced with permission from Ref. [117] Copyright 2020, John Wiley & Sons. (B) Scheme illustration of the effects of DOX@Exos-PH20-FA on the modulation of the TME, which leads to enhanced DDS uptake by the tumor and conversion of the immune microenvironment from immunosuppressive to immunosupportive to favor cancer therapy. Furthermore, Exos-PH20-FA directly reduces the accelerated migration of tumor cells triggered by HA degradation. Reproduced with permission from Ref. [122] Copyright 2021, Elsevier.

Fig. 8

(A) Schematic of synergistic photodynamic-immunotherapy mediated by PHD@PM. (a) The PHD@PM preparation procedure. (b) The mechanism underlying PDT-induced ICD and simultaneous PD-L1 blocking is mediated by PHD@PM. Reproduced with permission from Ref. [130] Copyright 2021, John Wiley & Sons. (B) Schematic illustration of the (a) preparation of the R@P-IM nanovaccine and (b) CRT exposed on the surface of the intratumoral-injected nanovaccine communicates an “Eat Me” sign to induce DCs to take up the nanovaccine. Reproduced with permission from Ref. [131] Copyright 2021, American Chemical Society.

Fig. 9

Fused membranes of 4T1 tumor cells and dendritic cells (DCs) camouflaged nanoplatforms for synergistic NIR-II photothermal immunotherapy. a) Preparation of SPNU, SPNT, and SPNE. b) SPNE mediated multicellular engagement, immune activation, and NIR-II photothermal effects. DAMPs, damage-associated molecular patterns. TLR, Toll-like receptor. MHC-I, major histocompatibility complex class I molecule. TCR, T-cell receptor. c) SPNE-induced immune activation and systemic immune responses for NIR-II photothermal immunotherapy. Reproduced with permission from Ref. [138] Copyright 2021, John Wiley & Sons.

Fig. 10

In vitro cytotoxicity and mechanism of ferroptosis induced by Fe₃O₄-SAS@PLT. (a) Cell viability of 4T1 cells treated with different concentrations of free SAS, Fe₃O₄, Fe₃O₄-SAS, and Fe₃O₄-SAS@PLT, respectively; n = 6. (b) Cell viability of Fe₃O₄-SAS@PLT-treated 4T1 cells in the presence of Fer-1 and DFO, respectively; n = 6. (c) Representative CLSM images of 4T1 cells stained with DCFH-DA in different groups (SAS, Fe₃O₄, Fe₃O₄-SAS, v-SAS@PLT, Fe₃O₄-SAS@PLT + Fer-1, and Fe₃O₄-SAS@PLT + DFO groups). (d) Quantification of total ROS, superoxide, hydroxyl peroxide, and hydroxyl radical by using appropriate fluorescent probes; n = 3. (e) Flow cytometry analysis of lipid peroxidation in different formulation-treated 4T1 cells by using a C11-BODIPY fluorescent probe. (f) Intracellular GSH levels in 4T1 cells treated with different formulations (SAS, Fe₃O₄, Fe₃O₄-SAS, Fe₃O₄-SAS@ PLT, Fe₃O₄-SAS@PLT + Fer-1, and Fe₃O₄-SAS@PLT + DFO groups); n = 3. (g) Intracellular XcT and GPX4 expression in 4T1 cells treated with different formulations including (1) Control, (2) SAS, (3) Fe₃O₄, (4) Fe₃O₄-SAS, (5) Fe₃O₄-SAS@PLT, (6) Fe₃O₄-SAS@PLT + Fer-1, and (7) Fe₃O₄-SAS@PLT + DFO; n = 3. Untreated 4T1 cells were taken as a control. ns represented no significance, *p < 0.001. Reproduced with permission from Ref. [148] Copyright 2020, John Wiley & Sons.

Fig. 11

Schematic illustration of PCN@FM for combined tumor therapy. (a) The preparation process of PCN@FM; and (b) combination between irradiation-mediated PDT and FM- and ICD-induced immunotherapy toward primary tumor and distant tumor therapy. Reproduced with permission from Ref. [97] Copyright 2019, John Wiley & Sons.