Chemotherapy is a widely used and effective adjuvant treatment for cancer, and it has unavoidable damage to female fertility, with statistics showing 38% of women who have received chemotherapy are infertile. How to reduce fertility toxicity while enhancing the oncologic chemotherapy is a clinical challenge. Herein, co‐delivery micelles (BML@PMP) are developed, which are composed of a reduction‐sensitive paclitaxel prodrug (PMP) for chemotherapy and a CHEK2 inhibitor (BML277) for both fertility protection and chemotherapy enhancement. BML@PMP achieves fertility protection through three actions: (1) Due to the enhanced permeability and retention (EPR) effect, BML@PMP is more enriched in the tumor, while very little in the ovary (about 1/10th of the tumor). (2) Glutathione (GSH) triggers the release of PTX, and with low levels of GSH in the ovary, the amount of PTX released in the ovary is correspondingly reduced. (3) BML277 inhibits oocyte apoptosis by inhibiting the CHEK2‐TAp63α pathway. Because of the different downstream targets of CHEK2 in tumor cells and oocytes, BML277 also enhances chemotherapeutic efficacy by reducing DNA damage repair which is activated through the CHEK2 pathway. This bidirectional effect of CHEK2 inhibitor‐based co‐delivery system represents a promising strategy for improving oncology treatment indices and preventing chemotherapy‐associated fertility damage.

Ovarian aging is characterized by a progressive decline in ovarian function. With the increase in life expectancy worldwide, ovarian aging has gradually become a key health problem among women. Over the years, various strategies have been developed to preserve fertility in women, while there are currently no clinical treatments to delay ovarian aging. Recently, advances in biomaterials and technologies, such as three-dimensional (3D) printing and microfluidics for the encapsulation of follicles and nanoparticles as delivery systems for drugs, have shown potential to be translational strategies for ovarian aging. This review introduces the research progress on the mechanisms underlying ovarian aging, and summarizes the current state of biomaterials in the evaluation and treatment of ovarian aging, including safety, potential applications, future directions and difficulties in translation. Graphical Abstract

Chemotherapy is often a cause of premature ovarian insufficiency and infertility since the ovarian follicles are extremely sensitive to the effects of chemotherapeutic agents. Different chemotherapeutic agents with varying mechanisms of action may damage ovarian function differently. Taxanes are widely used in clinical cancer treatment, but the specific reproductive toxicological information is still controversial. This review described the impact and duration of taxanes on ovarian function in women and analyzed the possible reasons for different conclusions. Furthermore, the toxicity of taxanes on ovarian function and its possible mechanisms were discussed. The potential protective strategies and agents against ovarian damage induced by taxanes are also reviewed.

Our understanding of how aging affects the cellular and molecular components of the human ovary and contributes to age-related fertility decline is still limited. Here, we link single-cell RNA sequencing and spatial transcriptomics to characterize human ovarian aging. Changes of the molecular signatures of eight types of ovarian cells during aging were defined. We combined single cell types with their spatial location information to divide ovarian granulosa cells into three subtypes and theca & stroma cells into five subtypes. Further analysis revealed increased cellular senescence with age and characterized the transcription factor FOXP1 as a master regulatory gene during ovarian aging. Inhibition of FOXP1 in ovarian cells increased cellular senescence which was alleviated by pharmacological treatment with quercetin or fisetin. These findings provide a comprehensive understanding of the spatiotemporal variability of human ovarian aging, providing resources for developing new diagnostic biomarkers and therapeutic strategies against ovarian aging.

Metronomic photodynamic therapy (mPDT), which induces cancer cell death by prolonged intermittent continuous irradiation at lower light power, has profoundly promising applications. However, the photobleaching sensitivity of the photosensitizer (PS) and the difficulty of delivery pose barriers to the clinical application of mPDT. Here, we constructed a microneedle-based device (Microneedles@AIE PSs) that combined with aggregation-induced emission (AIE) PSs to achieve enhanced mPDT for cancer. Due to the strong anti-photobleaching property of the AIE PS, it can maintain superior photosensitivity even after long-time light exposure. The delivery of the AIE PS to the tumor through a microneedle device allows for greater uniformity and depth. This Microneedles@AIE PSsbased mPDT (M-mPDT) offers better treatment outcomes and easier access, and combining M-mPDT with surgery or immunotherapy can also significantly improve the effectiveness of these clinical therapies. In conclusion, M-mPDT offers a promising strategy for the clinical application of PDT due to its better efficacy and convenience.

Semaphorins are a family of evolutionarily conserved morphogenetic molecules that were initially found to be associated with axonal guidance. Semaphorin 4C (Sema4C), a member of the fourth subfamily of semaphorins, has been demonstrated to play multifaceted and important roles in organ development, immune regulation, tumour growth and metastasis. However, it is completely unknown whether Sema4C is involved in the regulation of ovarian function. We found that Sema4C was widely expressed in the stroma, follicles and corpus luteum of mouse ovaries, and its expression was decreased at distinct foci in ovaries of mice of mid-to-advanced reproductive age. Inhibition of Sema4C by the ovarian intrabursal administration of recombinant adeno-associated virus (AAV)-shRNA significantly reduced oestradiol, progesterone and testosterone levels in vivo. Transcriptome sequencing analysis showed changes in pathways related to ovarian steroidogenesis and the actin cytoskeleton. Similarly, knockdown of Sema4C by siRNA interference in mouse primary ovarian granulosa cells (GCs) or thecal interstitial cells (TICs) significantly suppressed ovarian steroidogenesis and led to actin cytoskeleton disorganization. Importantly, the cytoskeleton-related pathway RHOA/ROCK1 was simultaneously inhibited after downregulation of Sema4C. Furthermore, treatment with a ROCK1 agonist after siRNA interference stabilized the actin cytoskeleton and reversed the inhibitory effect on steroid hormones described above. In conclusion, Sema4C may play an important role in ovarian steroidogenesis through regulation of the actin cytoskeleton via the RHOA/ROCK1 signalling pathway. These findings shed new light on the identification of dominant factors involved in the endocrine physiology of female reproduction.