Table 2 Regulation of biomaterial-based autophagy in tissue regeneration
From: Autophagy-modulating biomaterials: multifunctional weapons to promote tissue regeneration
Organ | Biomaterials | Target cell | Autophagy markers (downregulation [↓]/upregulation [↑]) | Autophagy mechanism | Tissue repair markers (downregulation [↓]/upregulation [↑]) | Biological effect | Ref |
|---|---|---|---|---|---|---|---|
Bone | Sr-doped micro/nano rough titanium implants | BMSCs | For osteogenic differentiation of BMSCs: LC3II/LC3I↑, P62↓ and Beclin-1↑ For osteoclast differentiation: LC3II/LC3I↓, P62↑and Beclin-1↓ | Not reported | For osteogenic differentiation of BMSCs: ALP↑, calcium nodules ↑ and Runx2, BMP-2, OCN and COL-1↑ For osteoclast differentiation: TRAF6, Ctsk and C-Fos↓ | Upregulated autophagy and osteogenic differentiation in BMSCs, downregulated autophagy and differentiation in osteoclasts in vitro, improved implant osseointegration, decreased active osteoclast development and upregulated autophagy in bone tissue cells in vivo | [137] |
Sr-doped 45S5 bioglass | BMSCs | In the early phase: LC3II/LC3I↑ and Beclin-1↑ In the late phase: LC3II/LC3I↓ and Beclin-1↓ | AKT/mTOR | ALP and calcium nodules ↑ | Improved autophagy and promoted osteogenic differentiation of OVX-BMSCs and bone regeneration in osteoporotic bone defects | [138] | |
Resveratrol and angiogenin-2 combined with PEGDA/TCS hydrogels | BMSCs and HUVECs | LC3II/LC3I↑, P62↓and Beclin-1↑ | Not reported | Ki67 ↑, CD31↑, ALP ↑, calcium nodules ↑and Runx2 and OPN↑ | Promoted BMSC differentiation and vascularization and tissue repair in the tibial defect through autophagy | [139] | |
Silver nanoparticle-loaded TiO2 nanotubes | RAW264.7 and MC3T3-E1 cells | LC3II/LC3I ↑and Beclin-1 ↑ | PI3K/AKT and GLUT1 | ALP, RUNX2, OCN and OPG ↑ | Activated autophagy, regulated bone immunity and promoted osteogenesis | [104] | |
Gold nanoparticles | Periodontal ligament stem cells (PDLSCs) | LC3II↑and P62↓ | Not reported | ALP, calcium nodules↑; RUNX2, OCN and COL-1↑ | Enhanced osteogenesis of PDLSC sheets by activating autophagy | [102] | |
Dicalcium silicate nanoparticles | BMSCs | LC3II/LC3I↑, P62↓and Beclin-1↑ | mTOR/ULK1 and WNT/β-catenin | Calcium nodules ↑ BMP2, UNX2 and OSX↑ | Enhanced bone formation and osteogenic differentiation by activating autophagy | [140] | |
Nanosized alumina particles and bortezomib | MG-63 cells | LC3↑ | Nf-κB | OPG↑ | Activated autophagy and inhibited apoptosis | [141] | |
Titanium implants with nanotopography | MC3T3-E1 cells | LC3II/LC3I↑ and P62↓ | YAP and β-catenin | ALP and Osx ↑ | Activated autophagy and promoted osteogenesis | [18] | |
Solid silica nanoparticles (SSN) | BMSCs | LC3II ↑ | ERK1/2 and AKT/mTOR | ALP, COLI, OPN, OPG, RUNX2 and OCN↑ | Improved osteogenic differentiation by increasing autophagy | [142] | |
Nanohydroxyapatite | MC3T3-E1 cells | LC3II/LC3I↑ | m-TOR | ALP, BMP2, OSC, BSP, BMP2 and RUNX2↑ | Modulated osteoblast differentiation by mediating autophagy in a dose-dependent manner | [143] | |
Sinomenine encapsulated within chitosan microspheres and photo-crosslinked GelMA hydrogels | Mouse chondrocytes | LC3↑ | Not reported | MMP13 and ADAMT-5 ↓, COL2A1 and AGGRECAN↑and safranin-O staining ↑ | Retarded the progression of surgically induced OA and ameliorated cartilage matrix degradation at least partially through autophagy | [117] | |
miR-100-5p-abundant exosomes | MSCs | LC3II↑and P62↓ | mTOR | Collagen II↑, MMP 13 and ADAMTS 5↓and safranin-O staining↑ | Protected articular cartilage from damage and ameliorated gait abnormality in mice with OA | [144] | |
Kartogenin/reduced graphene oxide@gelatin | ADSCs | LC3II/LC3I↑, Beclin-1↑and ULK1↑ | Not reported | Sox-9↑, Col II ↑, alcian blue staining ↑and toluidine blue staining↑ | Promoted chondrogenesis synergistically by modulating autophagy | [145] | |
Skin | Metal-organic frameworks | Mouse embryonic fibroblasts | LC3II/LC3I↑, P62↓, Beclin-1↑and ATG5↑ | mTOR | Cell apoptosis↓ | Reduced ROS production and induced cytoprotective autophagy | [146] |
MSCs | Endothelial progenitor cells | LC3II/LC3I↑, Beclin-1↑and ATG7↑ | ERK | wound size↓, CD31 ↑, tube formation↑and VEGF↑ | Enhanced full-layer cutaneous wound healing and promoted the paracrine secretion of VEGF in MSCs | [147] | |
PDGF-PLGA hydrogels | HUVECs and 3T3 cells | LC3II/LC3I↓ | Not reported | Migration rate, granulation tissue formation and collagen deposition↑ | Promoted the proliferation and migration of cells and accelerated the closure of full-thickness excision wounds by inhibiting autophagy | [34] | |
Sulfobetaine methacrylate hydrogels |  | LC3II↑and P62↓ | PI3K/Akt/mTOR | Wound size↓, granulation tissue ↑, collagen deposition↑, collagenI/III ↑, CD68↓ and CD206↑ Fibronectin ↑, laminin↑ and MMP-2↓ | Improved pressure ulcer healing by promoting ECM reconstruction by inducing autophagy | [118] | |
Chitosan/PVP/dihydroquercetin nanocomposite films | Hacat cells | LC3II/LC3I↑, Beclin-1↑, p62↓, ATG5↑and ATG7↑ | PI3K/Akt/mTOR | Wound size↓, granulation tissue ↑, collagen deposition↑ VEGF, CD31 and pankeratin↑ | Promoted wound healing by activating autophagy | [28] | |
Nerve | Polycaprolactone neural guide conduit loaded with melatonin | Sciatic nerve cells | LC3A/B↑; Beclin1 and LC3I↑and ATG3, ATG5 and ATG7↑ | Not reported | Sciatic function index↑, nerve conducting velocity↑, regenerated axon area↑ c-caspase↓ | Enhanced autophagy, reduced apoptosis and restored proliferation of neurons | [148] |
Single-walled carbon nanotubes | CRND8 glial cells | p-ULK1↓, LC3↑and p62↓ | mTOR | Lysosome number↑ active CatD↑ | Induced autophagy, restored lysosomal function and facilitated the elimination of autophagic substrates | [90] | |
Chitosan-based nanosweeper combined with PEGylated-GKLVFF and Beclin-1 peptide | N2a cells and hippocampal neurons | LC3II↑, p62↑and LC3↑ | Not reported | Soluble and insoluble Aβ42↓and escape latencies↓ | Induced autophagy and Aβ clearance, increased cell viability and rescued memory deficits | [149] | |
Nanosized polyethylene glycol loaded with a curcumin analog | N2a cells | LC3↑ | Not reported | α-syn↓ | Induced autophagy and clearance of α-syn | [150] | |
Gold nanoclusters with dihydrolipoic acid | BV2 cells | LC3II/LC3I ↑and P62 ↑ | Not reported | Arg-1 and CD206↑, iNOS↓NOX4 and ROS production↓ | Induced autophagy with the polarization of macrophages to the M2 phenotype and reduced oxidative stress caused by ROS | [151] | |
Graphene oxide-coated electrospun nanofibers loaded with methylene blue | Neural progenitor cells (NPCs) | LC3II↑ | Not reported | G0/G1 phase cells↑ p-tau S262↓ | NPCs entered the quiescence phase, and degeneration of p-tau was increased | [152] | |
Neuron-derived exosomes loaded with miR-21-5p | HT-22 neurons | LC3, P62 and Beclin-1↓ | Rab11a | caspase-3 and Bcl-2↓ | Inhibited autophagy and attenuated nerve injury | [153] | |
Europium hydroxide [EuIII(OH)3] nanorods | Neuro 2a, PC12 and HeLa cells | LC3II/LC3I ↑and P62↓ | Not reported | GFP-Htt (Q74)↓ | Enhanced the clearance of the huntingtin protein | [154] | |
Heart | Magnetic mesoporous silica-coated Fe3O4 nanoparticles loaded with N-acetylcysteine | Cardiomyocytes | p62↓ LC3II↓ | Not reported | LDH activity↓, MMP↑, caspase-3 and Bax↓; Bcl-2↑ MDA, 8-OHDG and 8-iso-PGF2α↓and GSH, CAT, GSH-Px and SOD↑ | Reduced apoptosis and ROS generation induced by Fe3O4 NPs by reducing autophagy | [155] |
Perfluorocarbon particles loaded with rapamycin | Cardiomyocytes | p62 ↓ BNIP3 and LC3II ↑ | mTOR | LVEF↑ | Increased cardiac contractile performance and LVEF | [156] | |
Kidney | Kidney injury molecule-1-Res NPs | Human proximal tubular epithelial cell line HK-2 | LC3II↑, Beclin-1↑and p62↓ | AMPK mTOR | Blood urea nitrogen↓, creatinine↓, NLRP3↓ IL-1β↓ | Suppressed the NLRP3 inflammasome by enhancing autophagy and ameliorated chronic kidney disease | [27] |
Extracellular vesicle (EV)-RGD (Arg-Gly-Asp) hydrogels | HK-2 cells and mouse macrophages RAW263.7 | LC3B↑ | miRNA let-7a-5p | SCr and BUN↓, Kim-1↓ | Elevated cell autophagy, improved renal function, decreased tubular injury and ameliorated histopathological impairments | [127] | |
Magnetic Fe3O4 nanoparticles with albumin (Fe3O4@BSA) |  | Autophagosome↑ | Rab7 | MMP-2↑, α-SMA↓, ALB, BUN and Scr↓, urinary protein and NAG↓ collagen accumulation↓ | Attenuated renal tubular injury and tubulointerstitial fibrosis | [157] | |
Ceria-zirconia nanoparticles | HK‑2 podocytes | LC3II/LC3I↑ | AKT/mTOR | ROS levels↓, cell apoptosis↓TGFβ1, fibronectin and α-SMA↓ | Reduced intracellular globotriaosylceramide accumulation and alleviated kidney injury | [158] | |
Lung | Rapamycin (mTOR) siRNA-loaded DNA nanotubes (DNA-NTs) | Pulmonary arterial smooth muscle cells (PASMCs) | LC3II/LC3I↑ | mTOR | Cell proliferation↓ | Efficiently delivered siRNA to PASMCs, leading to strong autophagy induction, and inhibited the proliferation of PASMCs | [159] |
mTOR siRNA-loaded spermidine/DNA tetrahedron nanoplatform | Bone marrow-derived macrophages (BMDMs) | LC3B↑and P62↓ | mTOR | M1 polarization↓ M2 polarization↑ | Exerted anti-inflammatory effects by promoting autophagy and phenotypic transition of macrophages and relieved acute lung injury | [17] | |
Liver | Nifedipine-loaded nanoparticles composed of poly(lactic-co-glycolic acid) (PLGA) | HepG2 cells | P62 and ubiquitin↓ | Not reported | Oil red O staining ↓, liver mass↓ average adipocyte area of epididymal white adipose↓ | Improved insulin resistance and hepatic steatosis through autophagy | [160] |
Superparamagnetic iron oxide nanoparticles (SPIONs) | RAW 264.7 cells | LC3B II and Beclin-1 ↑ | Cav1-Notch1/HES1 | AST ↓, ALT↓ | Promoted IL-10 expression and inhibited inflammation by activating autophagy in models of LPS-induced sepsis and liver injury | [161] |