Hydrogels are distinguished by their high hydration capacity and hydrophilicity (Figure 1). These properties arise from hydrophilic macromolecular networks formed by water-soluble polymers via chemical or physical crosslinking (Patel and Mequanint, 2011). Such networks can absorb up to 1,000-fold their dry weight in water, swelling in aqueous environments without dissolving (Chai et al., 2017). This creates an internal aqueous microenvironment that protects encapsulated cells and sensitive drug molecules, making hydrogels ideal for cell culture and drug encapsulation (Saludas et al., 2017).

The unique microporous architecture of hydrogels confers high permeability. Pore size and distribution can be precisely controlled through specific fabrication methods to achieve programmable release of loaded agents (Fazli et al., 2024). For example, incorporation of zinc oxide nanoparticles increases hydrogel porosity, water uptake capacity, thermal stability, and mechanical strength, thereby modulating the release kinetics of nettle extract and providing sustained therapeutic effects (Fazli et al., 2024). Consequently, hydrogel systems with these characteristics have been extensively utilized for drug delivery applications in andrology (Pishavar et al., 2021).

Biocompatibility of hydrogels is primarily determined by their constituent materials. Based on material origin, hydrogels are classified as synthetic, natural, or hybrid. Synthetic hydrogels offer precise tunability and robust mechanical properties; examples include acrylamide and its derivatives, Polyvinyl Alcohol (PVA), Polyacrylic Acid (PAA), and polyurethane-based hydrogels (Figure 2A) (Sennakesavan et al., 2020; Xia and Chen, 2022; Mohammad et al., 2024; Luthfianti et al., 2024; Elliott et al., 2004). Natural hydrogels derive from biomolecules and include Gelatin (GEL), agarose, collagen, polypeptides, pullulan, Chitosan (CS), and Hyaluronic Acid (HA) (Figure 2B) (Huang et al., 2020; Su et al., 2021; Yoo et al., 2020; Wollenberg et al., 2018; Pan et al., 2021; Xu et al., 2019; Wang et al., 2022). Hybrid hydrogels integrate two or more polymer types, combining the mechanical strength of synthetic materials with the intrinsic biocompatibility of natural materials to overcome limitations such as insufficient mechanical integrity of natural hydrogels and lack of bioactivity in purely synthetic systems (Xia and Chen, 2022; Saroia et al., 2018).

Formation of hybrid hydrogels is achieved via four primary strategies: Interpenetrating Polymer Networks (IPNs), blending, copolymerization, and layer-by-layer assembly (Figure 2C) (Vasile et al., 2020; Cai et al., 2021; Shymborska et al., 2023; Park et al., 2018). IPNs consist of two or more polymer networks interlaced at the molecular scale without covalent bonds, enhancing mechanical strength and stimuli responsiveness. Blending involves uniform mixing of distinct hydrogel polymers to balance their individual advantages. Copolymerization employs multiple monomers in a single polymerization reaction, allowing precise control over network composition at the molecular level. Layer-by-layer assembly is performed by alternately depositing oppositely charged polymers to build multilayered composite structures.

Because many hydrogel materials are composed of ECM components, they inherently exhibit high biocompatibility. Moreover, by mimicking the native tissue microenvironment during fabrication, both compatibility and structural stability are further enhanced, facilitating applications in tissue engineering and regenerative medicine (Naahidi et al., 2017). In andrology, this biocompatibility has been widely harnessed for drug-delivery systems and tissue-repair scaffolds (Ren Y. et al., 2023; Moon et al., 2023).

Hydrogels, as highly tunable smart materials, have physicochemical properties that can be precisely adjusted through variations in polymer composition, network architecture, and fabrication techniques, allowing customization for diverse biomedical applications (Wang Y. et al., 2025). Controllable parameters include swelling ratio, porosity, pH-responsiveness, temperature-responsiveness, photoresponsiveness, and electrical and magnetic properties, which confer distinct advantages over conventional materials as Figure 3 (Wu et al., 2024; Maiti et al., 2024; Amirthalingam et al., 2023). These physicochemical traits not only govern the hydrogel’s physical and chemical behavior but also directly influence its functional performance in drug delivery and tissue engineering contexts (De Nitto et al., 2024; Luo et al., 2023).

Natural hydrogels, distinguished by their unique architecture and high water content, are widely employed in andrological disease management (drug delivery) and male infertility therapy (tissue preservation, regeneration and repair) because of their excellent controlled-release performance, biocompatibility and tissue non-toxicity (Tan et al., 2024; Ahmed, 2015). Their clinical utility, however, is often constrained by weak mechanical strength and limited diffusion rates (Calvert, 2009). Synthetic hydrogels, produced through tailored fabrication techniques, can offset these shortcomings. Studies have demonstrated that double-network hydrogels—with two interpenetrating, highly cross-linked networks—exhibit orders-of-magnitude increases in strength, stiffness and toughness, thereby markedly improving the mechanical limitations of natural hydrogels (Zhang and Khademhosseini, 2017). In addition, topological design strategies that interlock polymer chains with figure-eight cross-linkers yield highly elastic hydrogels; the system developed by Wenz et al. achieved notably higher swelling capacity and fracture strain than conventional types, with a swelling ratio of up to forty-fold (Kali et al., 2016). Such high-strength synthetic hydrogels show great promise for repairing tissues exposed to harsh physiological environments, such as the urethra and bladder (Xiao et al., 2021). Nevertheless, despite advances in mechanical tuning, synthetic hydrogels often exhibit poor fatigue resistance, as irreversible breakage of intra- or intermolecular covalent bonds can occur within the network (Zhang and Khademhosseini, 2017). Given the respective limitations of natural and synthetic hydrogels, hybrid hydrogels—created by integrating multiple materials through sophisticated fabrication approaches—have emerged to provide better drug-release profiles and bioavailability (Omidian et al., 2025). This strategy introduces design complexity: different material combinations influence interfacial affinity, solubility, stability and release kinetics, thereby modulating drug-release behaviour. If processing conditions are not carefully controlled, the sustained-release potential may be diminished (Table 1) (Cirri et al., 2022).

PC treatment strategies aim for curative outcomes, a key challenge is the reduction of therapy-related toxicities. Owing to their outstanding biocompatibility, injectability for in-situ formation and tunable physicochemical responsiveness, hydrogels show unique promise in PC radiotherapy for lowering rectal toxicity, minimising side effects and enabling more precise irradiation.

BC is one of the most common malignancies worldwide and presents significant challenges due to high recurrence rates and substantial burdens on healthcare systems (Lopez-Beltran et al., 2024). BC is classified into non–muscle-invasive BC and muscle-invasive BC. Standard treatments—transurethral resection of bladder tumor and radical cystectomy—are often accompanied by complications such as urinary incontinence and bladder dysfunction, which markedly impair patient quality of life (Alfred et al., 2024). Recently, immunotherapy has emerged as a promising approach for BC treatment. Immune Checkpoint Inhibitors (ICIs), such as programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) antagonists, provide bladder-preserving options by restoring tumor-specific T-cell responses through PD-1/PD-L1 blockade and have demonstrated significant antitumor efficacy (Liu et al., 2024; Rhea et al., 2021). However, ICI monotherapy is limited by high dosage requirements, development of immune tolerance, and immune-related toxicities (Liu et al., 2024). To address these challenges, a Shikonin–Ferric Ion (Fe³⁺) Nanocomposite Hydrogel System (SHFe) was developed to induce ferroptosis-mediated immunogenic cell death. Shikonin encapsulation within SHFe stabilizes the molecule, enhances bioavailability, and enables sustained locoregional delivery. When SHFe is formulated with Tragacanth Gum (SHFe@TG), intravesical drug retention is extended to 72 h. In combination with a PD-1 inhibitor, SHFe@TG synergistically inhibits the Phosphoinositide 3-Kinase–Protein Kinase B (PI3K–AKT) signaling pathway, thereby suppressing BC cell proliferation (Zhao et al., 2025). Furthermore, a Recombinant Oncolytic Adenovirus–Loaded Hydrogel (Adv-CRB3@gel) was engineered to co-deliver an edited CRB3 gene and Granulocyte–Macrophage Colony-Stimulating Factor (GM-CSF). This system not only inhibits BC tumor cells and recruits T cells to remodel the tumor immune microenvironment and enhance tumor antigen–specific immune responses, but it also synergizes with PD-L1 blockade to directly kill BC cells, resulting in marked suppression of tumor proliferation, migration, and invasion (Figure 4) (Zhang WQ. et al., 2024).

ED affects over 150,000,000 men worldwide (Wang CM. et al., 2023). Current ED therapies include oral pharmacotherapy, shockwave therapy, hormone replacement therapy, vacuum erection devices, intracavernosal injections, vascular surgery, and penile prosthesis implantation (Ren Y. et al., 2023). However, these approaches are limited by low bioavailability, systemic adverse effects, poor patient compliance, invasiveness, and narrow applicability (Salonia et al., 2021; Hatzimouratidis et al., 2016; Atipairin et al., 2020). In contrast, hydrogels offer multiple advantages for ED treatment.

Neurogenic ED results from impaired neural signaling to the corpora cavernosa (Yang et al., 2024). Although phosphodiesterase type 5 inhibitors are first-line agents for ED, they are ineffective in neuronally induced ED (Salonia et al., 2021). Hydrogels have been investigated as biomaterial carriers to promote nerve regeneration and repair nervous system injury associated with cavernosal neuropathy (Bellotti et al., 2021; Nih et al., 2016). A Sonic Hedgehog (SHH)-loaded peptide amphiphile nanofiber hydrogel (SHH-PA) delivers SHH protein and, via a caspase-9-dependent mechanism, inhibits intrinsic caspase-9 and extrinsic caspase-8 signaling, reducing smooth muscle apoptosis and collagen deposition to improve erectile function (Figure 5A) (Martin et al., 2021). Similarly, a sprayable conductive adhesive hydrogel (GACM) with high adhesion and anti-swelling properties conforms to injured nerves to form an electrical bridge, facilitating nerve regeneration and suppressing macrophage-mediated inflammation to restore cavernosal innervation and erectile function (Figure 5B) (Wang et al., 2024).

Erectile Dysfunction in Type 1 Diabetes Mellitus (T1D-ED) is a common complication of diabetes mellitus (Wessells et al., 2018). Stem cell therapies have been explored for T1D-ED but are hindered by hemodynamic washout of cells into cavernosal venules, especially in the flaccid state (Aziz et al., 2010; Huang et al., 2010). To address this, a self-healing hydrogel composed of benzaldehyde-terminated PEG and Glycol Chitosan (GCS) (CHO-PEG/GCS) was engineered to encapsulate Adipose-Derived Stem Cells (ASCs), prolong cellular retention, and synergize angiogenic, antifibrotic, and antiapoptotic effects to restore erectile function in diabetic ED models (Figure 5C) (Yan et al., 2020). These studies demonstrate the broad potential of hydrogels for neurovascular repair in ED.

In recent years, hydrogel technologies have demonstrated significant potential in male infertility treatment and reproductive tissue engineering due to their biomimetic properties and tunable physicochemical characteristics, particularly in sperm selection and release and in testicular tissue transplantation and regeneration. Male-factor infertility accounts for 30%–50% of infertility cases and has increased globally (Eisenberg et al., 2023). Assisted reproductive technologies, including Intracytoplasmic Sperm Injection (ICSI), have markedly improved pregnancy rates (Esteves et al., 2018). However, ICSI bypasses the natural sperm selection mechanisms of the female reproductive tract and the oocyte’s zona pellucida barrier (Sánchez-Calabuig et al., 2014), Defective sperm can lower fertilisation rates, impair embryo quality and markedly raise the risk of miscarriage, thereby greatly increasing the likelihood of ART failure and potentially posing unknown long-term health risks to offspring (Li et al., 2023). Consequently, selecting high-quality sperm has become a pivotal challenge.

HA, a natural polymer synthesized by various cell types in reproductive and nonreproductive tissues, has been shown to selectively bind sperm with high motility and intact acrosomes, thereby improving ICSI outcomes (Casillas et al., 2018; Canepa et al., 2019). A semi-interpenetrating polymer network hydrogel composed of poly(N-isopropylacrylamide-co-hydroxyethyl methacrylate) (PNIPAM-HMA) and HA was developed to achieve charge-mediated sperm capture. In bovine models, this hydrogel achieved 50% specific attachment of bull spermatozoa. Following hyaluronidase treatment, 47% of bound sperm were released; these released sperm exhibited 70% progressive motility and maintained high plasma-membrane integrity (Figure 6) (Blois et al., 2021).

Testicular tissue autotransplantation and in vitro maturation techniques have garnered significant attention, particularly for prepubertal pediatric oncology patients who do not produce sperm and whose future fertility may be irreversibly compromised by chemotherapy and radiotherapy (Wyns et al., 2011; Wyns et al., 2015). However, limitations in current cryopreservation protocols predispose grafts to ischemic injury during revascularization, substantially reducing spermatogonial survival and viability posttransplantation (Poels et al., 2013; Van Saen et al., 2013). The spatiotemporal delivery of Vascular Endothelial Growth Factor (VEGF) is a critical determinant of graft outcome (Cao et al., 2005). In murine models, alginate hydrogels loaded with testicular tissue and VEGF were histologically analyzed posttransplantation; VEGF-laden grafts exhibited significantly increased microvascular density and reduced undifferentiated spermatogonial counts, demonstrating that alginate hydrogels effectively preserve spermatogonia and enhance posttransplant recovery of testicular architecture (Poels et al., 2016).

Spermatogenesis—the proliferation and differentiation of Spermatogonial Stem Cells (SSCs) within seminiferous tubules—requires efficient culture systems for fertility preservation and assisted reproductive technology applications (Stukenborg et al., 2008; Zhang J-Y. et al., 2024). Conventional SSC culture relies on feeder-layer cells, resulting in inefficiencies and contamination risks (Yang et al., 2020). Decellularized Testicular Matrix (DTM) hydrogels have emerged as promising scaffolds for generating testicular organoids (Saldin et al., 2017). A three-dimensional (3D) culture system utilizing DTM hydrogel was developed and seeded with murine SSCs. Compared with feeder-layer methods, SSC proliferation rates were markedly increased, and gene-expression profiles matched those of native SSCs, offering a feeder-free approach to more efficient in vitro SSC expansion and differentiation (Yang et al., 2020). Furthermore, the incorporation of epididymal cells and glial cell line–derived neurotrophic factor into the DTM hydrogel system was shown to enhance postthaw SSC proliferation. This composite system significantly reduced caspase-3 expression and upregulated miR-21, resulting in increased spermatogenic cell numbers, indicative of antiapoptotic effects and enhanced SSC regenerative capacity (Rahbar et al., 2024).

A semi-interpenetrating poly(N-isopropylacrylamide-co-hydroxyethyl methacrylate)/hyaluronic-acid (PNIPAM-HMA/HA) network captures motile, acrosome-intact sperm via charge interactions; brief hyaluronidase treatment then releases the enriched sperm population for ICSI.

Hydrogels formulated with biomaterials such as alginate, Silk Fibroin (SF), and Bladder Acellular Matrix (BAM) exhibit exceptional biocompatibility, tunable physicochemical characteristics, and cell‐adhesive and–differentiative capacities, conferring high stability even in hostile environments. Consequently, they hold significant promise for bladder and urethral repair and reconstruction.

Chronic inflammation of the bladder and prostate remains inadequately managed by current therapies. Novel hydrogel systems, formulated via diverse crosslinking strategies, offer sustained drug release, enhanced inflammatory repair, and improved barrier penetration, providing efficient treatment avenues for chronic urogenital inflammation.

Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is characterized by pelvic pain, lower urinary tract symptoms, and bladder hypersensitivity (Payne et al., 2007). Intravesical injection of OnabotulinumtoxinA (BTX-A) is an established therapy; however, the injection procedure can be extremely painful for IC/BPS patients and is associated with bleeding, infection, and urinary retention (Rappaport et al., 2018). Intravesical instillation has emerged as a less invasive alternative but is hampered by rapid drug washout and potential instillation-related adverse events (Krhut and Zvara, 2011). A temperature-responsive TC-3 hydrogel system (TC-3) was developed to deliver BTX-A via bladder instillation. Following treatment, patients exhibited significant reductions in pain visual analog scale scores, inflammatory index, problem index, and nocturia frequency at week 6. These findings indicate that the TC-3 hydrogel enables continuous intravesical BTX-A release while mitigating instillation-related side effects (Rappaport et al., 2018).

Hemorrhagic Cystitis (HC) is a debilitating inflammatory condition of the bladder characterized by hemorrhage and ulceration, often accompanied by severe pain, hematuria, and dysuria, which profoundly impair patient quality of life (D'Amico et al., 2022). HC can be classified into subtypes, with chemical HC typically induced by chemotherapeutic agents such as cyclophosphamide (Matz and Hsieh, 2017). Current treatments—including pharmacotherapy and surgical intervention—are limited by systemic side effects and risks of infection, anesthesia‐related complications, and prolonged recovery, respectively (Payne et al., 2013). A major challenge is maintaining robust adhesion and mechanical integrity of intravesical therapies in the bladder’s dynamic fluid environment under cyclic mechanical stresses. To address these obstacles, a Silk Fibroin Methacryloyl (SFMA)/tea polyphenol composite hydrogel was engineered via photopolymerization. This hydrogel exhibits strong mucoadhesive strength and excellent compressive resilience, enabling it to withstand cyclic bladder distension. In a cyclophosphamide‐induced rat HC model, SFMA/tea polyphenol hydrogels significantly reduced hematuria, suppressed interleukin-1β (IL-1β) expression, and upregulated CD31, CD63, and α-smooth muscle actin (α-SMA), thereby enhancing neovascularization and smooth muscle regeneration and accelerating tissue repair (Chen et al., 2024). Similarly, a Chitosan Methacryloyl (CHMA)/SFMA hydrogel system—produced via photoinitiated crosslinking and methacrylation—demonstrated high adhesive strength and rapid hemostasis on injured porcine bladder tissue. In vitro, the CHMA/SFMA hydrogel promoted microaggregate formation of ureteral epithelial cells and modulated macrophage polarization, facilitating inflammation resolution, accelerating angiogenesis and myogenesis, and improving HC-associated bladder damage (Yao et al., 2024).

Chronic Prostatitis (CP) is a syndrome characterized by pelvic pain and lower urinary tract symptoms (Rees et al., 2015). More than 90% of CP cases are classified as Chronic Nonbacterial Prostatitis (CNP) (Cyril et al., 2022). Current treatments for CNP include antibiotics, alpha-adrenergic blockers, and nonsteroidal anti-inflammatory drugs (Franco et al., 2019). Emodin (EMO), a natural anthraquinone derivative, exhibits anti-inflammatory, antioxidant, and antifibrotic properties; however, its therapeutic efficacy is limited by poor permeability across the Blood–Prostate Barrier (BPB) (Xia et al., 2021). To overcome this barrier, a triple-targeted, thermosensitive rectal hydrogel nanodelivery system was engineered by dialysis and electrostatic adsorption to encapsulate EMO. This system targets lactoferrin receptors on intestinal epithelial NCM460 cells and prostate epithelial RWPE-1 cells, as well as CD44 receptors on macrophages, thereby significantly enhancing cellular uptake and inhibiting Toll-Like Receptor 4/Nuclear Factor-κB (TLR4/NF-κB) signaling. Furthermore, the hydrogel penetrates the BPB and accumulates in the prostatic acini, resulting in marked reductions in inflammatory cytokines, oxidative stress markers, and fibrosis in a CNP rat model, all without significant systemic toxicity (Ye et al., 2024).

Hydrogel materials have been extensively investigated across major andrological fields—PC, BC, ED, reproductive medicine, urinary tract reconstruction, and genitourinary infections—and have also shown potential in treating Overactive Bladder (OAB).

OAB, which is characterized by detrusor smooth muscle overactivity leading to increased urinary frequency, urgency, and occasional incontinence, is conventionally managed with anticholinergic agents (Wein, 2003). Oxybutynin Hydrochloride (Oxy) reduces bladder contractility by blocking postganglionic muscarinic receptors, thereby lowering intravesical pressure and raising the micturition threshold; however, long-term oral administration is limited by systemic side effects (Escobar et al., 2021). To address these limitations, a composite hydrogel was engineered via dynamic Schiff-base crosslinking between aldehyde-functionalized oxidized dextran and carboxymethyl chitosan to encapsulate Oxy, enabling localized sustained release. In OAB rat models, intravesical administration of the Oxy-loaded hydrogel was found to significantly reduce systemic adverse effects, downregulate Orai1/STIM1 calcium-channel proteins, and improve urodynamic parameters, demonstrating a promising targeted drug-delivery strategy for OAB therapy (Sun et al., 2022).

PC 5-year and 10-year survival rates are estimated at 65%–90% for patients diagnosed at an early stage, making early detection and accurate identification of PC critical for selecting optimal treatment strategies (Damborska et al., 2017). Although diagnostic methods such as Enzyme-Linked Immunosorbent Assay (ELISA), Surface Plasmon Resonance Imaging (SPRI), and PSA testing are available, they remain invasive, time-consuming, costly, and procedurally complex (Liu et al., 2016). Consequently, a noninvasive assay is urgently needed to replace these traditional approaches. Elevated urinary sarcosine levels have emerged as a novel biomarker of PC cell growth (Sreekumar et al., 2009). A 3D hydrogel was fabricated by borax cross-linking regenerated cellulose (sourced from waste paper) with PVA, Carboxymethyl Cellulose (CMC), Graphene Oxide (GO), and 2-naphthoquinone-4-sulfonic acid sodium salt (NQS). This PVA/CMC/GO/NQS hydrogel exhibits a linear colorimetric response to sarcosine over a 0–100 µM range, shows negligible interference from urea or uric acid, and produces urinary assay results that correlate closely with mass spectrometry analyses, demonstrating its potential for noninvasive PC screening (Figure 7A) (Phookum et al., 2024).

A DNA-based hydrogel aptasensor employing Silver Nanoclusters with Aggregation-Induced Emission (AIE–AgNCs) was prepared to detect Prostate-Specific Antigen (PSA) without antibodies. Upon PSA binding, hydrogel collapse occurred and fluorescence intensity decreased proportionally, enabling quantification down to 4.4 pg mL⁻¹. The sensor exhibited minimal cross-reactivity with Immunoglobulin G (IgG) and provided a rapid, highly sensitive alternative to conventional immunoassays (Figure 7B) (Ahmadi-Sangachin et al., 2023).

PSA is a single-chain glycoprotein secreted by normal and malignant prostatic cells, and its serum levels are increased in PC (Meyer and Gorin, 2019). Although serum PSA concentration is widely utilized as a diagnostic biomarker for PC, it may lead to overdiagnosis and unnecessary prostate biopsies (Barry, 2001). Therefore, improved noninvasive and highly specific diagnostic methods are required. Detection of PC-associated biomarkers in bodily fluids such as urine is an attractive approach (Alix-Panabier̀es and Pantel, 2013). Exosomal microRNAs (miRNAs) have emerged as promising biomarkers for PC (Gao et al., 2019). A hydrogel-based HCR assay was developed for the detection of urinary exosomal miRNAs and validated clinically, demonstrating high sensitivity and specificity. This method quantified two urinary exosomal miRNAs—hsa-miR-6090 and hsa-miR-3665—with approximately 35-fold signal amplification and attomole-level limits of detection, indicating its potential as an adjunctive diagnostic tool for PC (Kim et al., 2021).

BC affects approximately 550,000 new cases annually and ranks among the top ten most common malignancies worldwide, imposing a severe burden on patient quality of life (Richters et al., 2020). Early detection and treatment of BC have been shown to achieve high cure rates (Kamat et al., 2016). Cystoscopy, CT, and MRI are the principal methods for early BC diagnosis; however, their invasiveness and ionizing‐radiation exposure limit routine use (Karaoglu et al., 2014).

Plasma‐based proteomic biomarker discovery is hindered by masking effects of high‐abundance proteins, and current depletion strategies are costly and time‐consuming (Anderson and Anderson, 2002). To address this, a protein‐equalization technique using Dithiothreitol (DTT) was coupled with Two‐Dimensional Sodium Dodecyl Sulfate–Polyacrylamide Gel Electrophoresis (2D‐SDS‐PAGE). Analysis of BC patient sera revealed overexpression of six proteins—albumin, gelsolin, fibrinogen γ chain, immunoglobulin α-1 chain C region, immunoglobulin α-2 chain C region, and haptoglobin—which were proposed as BC-associated biomarkers, offering a rapid, low-cost marker‐discovery strategy (Figure 8) (Araújo et al., 2018).

Optical fluorescence imaging within the second near-infrared window (NIR-II; 1,000–1,700 nm) has improved spatial resolution and tissue penetration for early tumor detection (Liu et al., 2022). However, NIR-II diagnostics require sufficient nanoprobe accumulation, and short bladder retention times limit effectiveness (Yoon et al., 2020). To overcome these challenges, an ultraminiature AuPd–Poly(Amidoamine)–Folic Acid (AuPd-P-FA) nanoprobe was incorporated into a temperature-responsive poly(amidoamine) hydrogel for bidirectional intravesical infusion. Folic acid targeting enhanced tumor-specific binding, shifted fluorescence emission to 1,250 nm, and increased quantum yield, thereby prolonging bladder residence and enriching signal in BC lesions—offering a novel noninvasive diagnostic strategy for BC (Ren SL. et al., 2023).

In drug-delivery contexts, smart responsive hydrogels address limitations of conventional chemotherapy (Table 2). DTX is a chemotherapeutic agent that induces apoptosis via phosphorylation of B-cell lymphoma 2 (Bcl-2) to inhibit tumour growth; however, its high lipophilicity and low aqueous solubility complicate its delivery (Shekari et al., 2025). Similarly, Doxorubicin (DOX) suffers from poor water solubility and systemic toxicity (Harris et al., 2002). To overcome these challenges, a star-shaped peptide supramolecular hydrogel responsive to zinc ions was developed. In situ self-assembly is triggered by the high zinc-ion concentration in prostatic tissue, enabling targeted DTX delivery and sustained release, and proliferation of DU-145 and PC-3 cells was inhibited in a dose-dependent manner (Tao et al., 2019). Silveira et al. formulated a composite thermosensitive hydrogel embedding DOX-loaded Mesoporous Silica Nanoparticles (MSNs). Using Pluronic F127s body-temperature–induced gelation, this intraperitoneal depot selectively adsorbs DOX within its nanopores and releases it via electrostatic interactions, resulting in a significant reduction in invasive PC incidence and decreased myocardial uptake of DOX (Silveira et al., 2016). These studies demonstrate the potential of hydrogel platforms to optimize PC therapy through targeted delivery and local controlled release.

Urothelial carcinoma ranks among the ten most common malignancies worldwide, with BC as the predominant subtype (Sung et al., 2021). Although therapeutic advances have markedly reduced mortality, postoperative recurrence remains a major clinical challenge (Rouprêt et al., 2023). Intravesical chemotherapy is recognized as an effective strategy to lower recurrence rates; however, its efficacy is hampered by the urothelial barrier, short drug residence time, and suboptimal targeting (GuhaSarkar et al., 2017). To address these limitations, a biodegradable in situ Gel–Liposome Hydrogel (LP-Gel) system was developed for bladder instillation. In this system, fluidic liposomes are embedded within a gellan gum hydrogel matrix and ion-triggered to form a cross-linked network, thereby enhancing permeability across the urothelial barrier and adhesion to the mucin layer. As a result, paclitaxel retention in the bladder was significantly prolonged (GuhaSarkar et al., 2017). Additionally, a polysaccharide-based supramolecular injectable hydrogel, termed Chitosan–Cyclodextrin Amphiphilic (CCA), was engineered via one-step co-encapsulation of CS, Sulfobutyl ether-β-Cyclodextrin (SBE-β-CD), and β-Cyclodextrin (β-CD) with DOX. In a murine BC model, this CCA hydrogel extended intravesical DOX retention and markedly enhanced its inhibitory effect on bladder tumour cells (Zhang C. et al., 2024).

Quercetin (Que), a natural polyphenolic flavonoid with potent anticancer activity and low toxicity, has been widely investigated for BC therapy. However, its poor aqueous solubility substantially reduces intravesical residence time (Pralhad and Rajendrakumar, 2004). To overcome this limitation, carrier systems were employed to enhance delivery and retention of Que. Shawky et al. evaluated various lipid vehicles for Que solubilization and used Poloxamer 407 (P407) as a thermosensitive in situ gel to create a mucoadhesive depot. This P407 formulation achieved Que penetration depths of up to 350 µm in ex vivo bladder tissue, extended retention to 24 h, and significantly inhibited T-24 cell viability (Shawky et al., 2022). Similarly, Rapamycin (RAP) was incorporated into both unmodified and folic acid–modified liposomes via thin-film hydration and preloading, and these liposomes were dispersed in a P407 thermosensitive hydrogel. This system doubled RAP cellular uptake and, through erosion-controlled release, increased tumor-inhibition rates by 60% in BC models (Yoon et al., 2019).

Intravesical instillation remains a cornerstone of BC treatment, yet most instilled drug is expelled during the first void, and the procedure can provoke urinary tract obstruction (Collado et al., 2000). To address these challenges, a floating hydrogel system was developed by generating microbubbles within the gel to reduce its density, allowing it to float atop urine. When hydrogel density falls below that of urine, buoyancy is maintained, thereby markedly reducing the risk of urinary tract blockage (Lin et al., 2016).

Sildenafil citrate is widely used to treat mild‐to‐moderate ED; however, it exhibits low oral bioavailability, frequent systemic adverse effects, and delayed onset of action (Elnaggar et al., 2011). A non-microemulsion hydrogel was formulated by incorporating isopropyl myristate and water with sildenafil citrate, resulting in a membrane permeation rate 1.97-fold higher than that of the pure drug solution, a 50% reduction in metabolite formation, and a shortened onset time (Atipairin et al., 2020). Intramuscular administration of Adipose-Derived Stem Cell Exosomes (ASC-Exo) has emerged as a promising ED therapy; however, the high vascularization of the corpora cavernosa limits ASC-Exo retention (Liang L. et al., 2022). To overcome this, an in situ–Polymerized Polydopamine Nanoparticle–Poly(Ethylene Glycol)–Poly(Lactic Acid) Thermosensitive Hydrogel (PDNPs–PELA) was developed and, when combined with photoacoustic imaging guidance, enabled precise, sustained delivery of ASC-Exo to the tunica albuginea, providing a novel approach to ED treatment (Liang L. et al., 2022).

All-Trans Retinoic Acid (atRA), an active metabolite of vitamin A, supports blood–testis barrier formation and promotes spermatogonial differentiation (Punab et al., 2017); however, its poor solubility, instability, and rapid metabolism limit its clinical application (Zheng et al., 2022). A thermosensitive hydrogel scaffold was engineered to encapsulate atRA, preventing its degradation and enabling sustained high-dose delivery in vivo, thereby enhancing spermatogonial differentiation, completion of meiosis, and release of mature sperm—a novel tissue-engineering approach for male infertility (Zarei et al., 2025).

Nonalcoholic Fatty Liver Disease (NAFLD) contributes to infertility. Although high-dose Quercetin (Que; ≥10 mg/kg/day) exerts anti-inflammatory, anti-apoptotic, and antioxidant effects in NAFLD (Khaki et al., 2010), pro-oxidant activity at higher doses may impair fertility (Ranawat et al., 2013). To address this, a bigel hydrogel composed of cottonseed oil, hempseed oil, and acacia gum was formulated for controlled Que release, attenuating its oxidative toxicity. In NAFLD rat models, this Que-loaded bigel significantly reduced sperm abnormalities and DNA fragmentation rates, restored serum testosterone levels, and enhanced spermatogenesis (Mousavi et al., 2021).

SCI induces oxidative damage mediated by Reactive Oxygen Species (ROS), which elevates sperm DNA fragmentation and impairs fertility (Gosálvez et al., 2022). Erythropoietin (EPO) demonstrates anti-apoptotic, antioxidant, and anti-inflammatory effects via activation of antioxidant enzymes and inhibition of lipid peroxidation but suffers from inefficient in vivo delivery (Zhang et al., 2022). A chitosan/alginate hydrogel was developed for local EPO delivery following SCI. In treated rats, sperm motility was significantly improved and testicular malondialdehyde levels were decreased, indicating that the EPO-loaded hydrogel enhances therapeutic outcomes for SCI-related infertility (Rasekh et al., 2025).