De novo design of a nanoregulator for the dynamic restoration of ovarian tissue in cryopreservation and transplantation

Abstract

The cryopreservation and transplantation of ovarian tissue underscore its paramount importance in safeguarding reproductive capacity and ameliorating reproductive disorders. However, challenges persist in ovarian tissue cryopreservation and transplantation (OTC-T), including the risk of tissue damage and dysfunction. Consequently, there has been a compelling exploration into the realm of nanoregulators to refine and enhance these procedures. This review embarks on a meticulous examination of the intricate anatomical structure of the ovary and its microenvironment, thereby establishing a robust groundwork for the development of nanomodulators. It systematically categorizes nanoregulators and delves deeply into their functions and mechanisms, meticulously tailored for optimizing ovarian tissue cryopreservation and transplantation. Furthermore, the review imparts valuable insights into the practical applications and obstacles encountered in clinical settings associated with OTC-T. Moreover, the review advocates for the utilization of microbially derived nanomodulators as a potent therapeutic intervention in ovarian tissue cryopreservation. The progression of these approaches holds the promise of seamlessly integrating nanoregulators into OTC-T practices, thereby heralding a new era of expansive applications and auspicious prospects in this pivotal domain.

Keywords: Nanoparticle; Nanoregulators; Ovarian system; Ovarian tissue cryopreservation and transplantation; Reproductive system; Transplantation.

Fig. 1

Dynamic repair of OTC-T by nanoregulators. In the process of ovarian tissue cryopreservation and transplantation, nanoregulators effectively inhibit the formation of ice crystals, promote angiogenesis in the transplanted tissues, reduce oxidative stress damage in the tissues, monitor the survival status of the transplanted tissue, and eliminate tumor cells within the transplanted tissue

Fig. 2

A The basic structure of the female reproductive system. B Apart from vascular and neural structures within the ovarian stroma, the primary constituents of the ovary include primordial follicles located in the cortex, as well as follicles at various stages of development. These follicles undergo maturation and eventually lead to the formation of ova through the process of ovulation [42]

Fig. 3

Major applications of ovarian hormones in female physiology and health. The secretion of ovarian hormones is mainly affected by the hypothalamic–pituitary–ovarian axis, and the secreted ovarian hormones such as estrogen, progesterone, androgen, and other hormones and growth factors play an important role in promoting the development of secondary sexual characteristics, maintaining fertility, maintaining youthful state, and preventing perimenopausal symptoms such as osteoporosis

Fig. 4

Ovarian tissue cryopreservation-transplantation process and challenges. Ovarian tissue cryopreservation-transplantation process: the ovaries are removed, the medulla is removed, the cortex is prepared, and the cortex tablets are frozen and thawed for orthotopic or ectopic transplantation [76]. Challenges in this process include: a toxicity of cryoprotectants. b Ischemic damage caused by early lack of vascular support. c Fatal damage to cells caused by ice crystals. d Oxidative stress damage after revascularization. e Risk of transplant reinfection caused by tumor contamination

Fig. 5

Ice crystal formation process and ice suppression mechanisms of common nanoregulators [141, 142]. A Ice crystal formation process. B Hydroxyapatite nanoparticles promote the entry of the extracellular cryoprotectant alginate into the cell. C WSe2-PVP NPs regulate ice crystal formation and promote ice crystal melting through the synergistic effects of hydrogen bond formation, adsorption inhibition, and photothermal conversion. D Graphene oxide inhibits ice crystal growth and recrystallization through the formation of hydrogen bonding with ice crystals, which results in bending of the ice crystal surface

Fig. 6

Mechanism of different types of zirconium-based metal and organic frame-based nanoregulators (MOF NPs) inhibiting ice crystal growth [145, 146]. A Schematic illustration of the solvothermal synthesis of MOF-801 NPs. B The formation process of MOF-808 NPs. C MOF-801 NPs as a cryoprotectant for preventing cell injury caused by ice crystal growth during cell freezing and thawing (left). Ice recrystallization inhibition effect of MOF-801 NPs by controlling the NPs size and introducing ice-binding amino acids that affect the micro curvature on the ice surface. The anchored water molecules allow the MOF-801 NPs to adsorb well to certain ice planes (right). D MOF-808 NPs form hydrogen bonds with water molecules to inhibit the growth of ice crystals. E The equilibrium of adhesion and separation between MOF-808 NPs and the ice surface makes it a “catalyst”, which accelerates the exchange of water molecules at the interface between ice and free water, thus promoting the melting of ice crystals

Fig. 7

Application and principle of nano-rewarming technology. A zebrafish embryo cryopreservation and laser gold nanorods (GNR) rewarming. Laser GNR warming yields rapid and uniform warming inside the embryo to outrun any ice formation [161]. B Fe₃O₄ nanoparticles for magnetic induction heating (MIH) to enhance rewarming of vitrification-cryopreserved human umbilical cord matrix mesenchymal stem cells (h-UCMMSCs) [164]. C Preantral follicles cryopreservation and nanometer warming combining magnetic induction heating (MIH) and laser-induced PAF heating (LIH) [163]

Fig. 8

Monitoring the survival rate of ovarian transplantation by AMH targeted nano-bubbles [137]. A Schematic of NBAMH and their targeting ability to rat ovarian granulosa cells expressing AMH. B Production and purification process of NBAMH. C Representative bright-field micrographs of NBs, NB IgG, and NBAMH bound to ovarian granulosa cells. D Representative B-mode and ultrasound molecular imaging of ovarian tissue by injection of NBAMH or NBs at different times after transplantation (3, 5, 7, and 10 days). E The quantitative analysis of signal intensity from A. Stronger signal intensity was observed in the NBAMH group relative to the NBs group from days 5 to 10 after transplantation. *P < 0.05

Fig. 9

Schematic diagram of the synthesis process and function of NO-releasing PEG-PLGA nanoparticles. A Polymerization of mPEG-PLGA from mPEG, lactide, and glycolide. Illustration of NO-NPs by the double-emulsion method containing DETA NONOate as the NO donor; B a schematic diagram of the release of NO nanoparticles from the ovary coated with fibrin hydrogel [184]. Nanoparticles release NO into the area around the ovary through the fibrin hydrogel matrix, stimulating blood vessels in the host to produce new blood vessels

Fig. 10

Self-produced hydrogen gas-powered magnesium micro-motor for the treatment of rheumatoid arthritis and acute ischemic stroke [215, 216]. A Schematic diagram of Mg-HA motor driven by self-produced hydrogen actively producing hydrogen under the guidance of ultrasound for RA treatment. B Schematic illustration of the fabrication of Mg–HA motors. C Schematic illustration of HPMs fabrication. D Mechanism of the H₂-mediated RA curative effect by Mg–HA motors. Active H₂ alleviates RA progression by ROS scavenging and further attenuates inflammation along with inflammatory cytokines. E Schematic illustration of HPMs as in situ H₂ generator for ischemic stroke remedy by active H₂ delivery to scavenge ROS and alleviate oxidative stress

Fig. 11

Nano-vesicles loaded with OR141 successfully eliminated chronic myeloid leukemia cells from sheep ovarian fragments by PDT in vitro [234]. A Preparation and characterization of vesicles containing OR-141 (ORN). B Evaluation of the efficacy of ORN–PDT using tumor models in ovarian tissue fragments; and C evaluation of PDT specificity using ovarian biopsies from young patients

Fig. 12

Damage to various systems by nanoparticles

Fig. 13

The main mechanism of toxic damage of nanoparticles to the female reproductive system. The toxicity of nanoparticles is mainly related to the size, charge, and shape of nanoparticles, which produce a large amount of reactive oxygen species to cause oxidative stress, resulting in mitochondria, DNA damage, cell cycle arrest, and so on, resulting in impaired reproductive damage