The lower genitourinary (GU) system refers to the urinary and reproductive organs apart from the kidney and ureter, such as the urethra, bladder, ovaries, uterus, vagina, scrotum, penis, and testes [1]. Lower GU trauma, usually caused by disease, accident, or iatrogenesis, has long been an important medical problem because the affected tissues generally fail to regenerate after injury, resulting in serious urinary, sexual, reproductive, and psychological consequences ^[2][3][4][2,3,4]. Therefore, improved strategies are urgently needed for the structural and functional reconstruction of damaged lower GU tissues.

Regenerative medicine, a multidisciplinary field that seeks to efficiently repair and regenerate injured tissues after trauma, has emerged as an attractive option for the treatment of lower GU damage ^[5][6][7][5,6,7]. Further, the use of bioactive agents (e.g., drugs, growth factors, cytokines, hormones, inhibitors, genes, and even living cells) to modulate cellular behavior and treat tissues may help improve current regenerative medicine approaches ^[8][9][10][8,9,10]. However, the direct application of bioactive agents in regenerative medicine is limited by their lack of stability, solubility, and ease of migration from the application site, making them ineffective for sustained treatment ^[5][11][5,11]. A delivery system refers to a device or formulation that enables spatiotemporal controlled release of active substances with adequate dosage and correct form at the target site ^[12][13][14][12,13,14]. Delivery systems aim to enhance the bioavailability of active substances, extend the duration of pharmacological action, increase treatment efficacy, and reduce adverse effects, thereby, acting as an important driving force for regenerative therapy [13].

However, regarding the delivery of active compounds, there is still a significant gap for improvement in loading efficiency, stability, therapeutic activity, and their spatiotemporal controlled release profile. Therefore, various exploration steps have been taken to develop sophisticated bioactive agent delivery systems focused on the types of biomaterials, delivery systems, and loading strategies. For instance, to endow biomaterials with additional characteristics that are beneficial to regenerative therapies, different composite materials, crosslinking methods, and chemical modifications have been developed ^{[15][16][17][18]}[15,16,17,18]. Furthermore, fabrication methods which may affect drug encapsulation, release, and biological efficacy, such as cell exosome production, three-dimensional (3D) printing, electrospinning, and microfluidics, have been used to produce diverse forms of delivery systems for the sequential delivery of therapeutic substances ^{[19][20][21][22][23]}[19,20,21,22,23]. In addition, many types of loading strategies, such as adding stabilizing excipients, covalent immobilization, in vitro loading, and structure optimization have been utilized to enhance bioavailability and prevent burst release ^{[24][25][26][27]}[24,25,26,27].

2. Classification of Biomaterials Used in Delivery Systems

A delivery system generally utilizes biomaterials as carriers to embed, deliver, and release bioactive substances at the desired site under controlled conditions ^[28][29][28,29]. Among them, inorganic and organic biomaterials are popular in delivery system-based regenerative medicine.

2.1. Inorganic Biomaterials

Inorganic biomaterials, including but not limited to metals, metallic oxides, and glasses, have been explored to fabricate delivery systems for soft tissue therapeutic applications. Metals and metallic oxides are considered to be potential carriers because of their well-defined structures and ease of chemical functionalization [30]. In addition to their carrier function, some metals or metallic oxides, such as gold, silver, iron oxide, zinc oxide, and cerium oxide, possess interesting features such as antibacterial activity, antioxidant properties, and the capacity to magnetically drive macrophage polarization ^[31][32][31,32]. Iron oxide nanoparticles are an excellent example of an inorganic biomaterial that has been intensively studied for use in regenerative therapy. Wu et al. fabricated basic fibroblast growth factor (bFGF)-loaded heparin dopamine conjugate-coated Fe₃O₄ nanoparticles (bFGF-HDC@Fe₃O₄) through surface immobilization [25]. The stability and bioactivity of bFGF was tested by evaluating the effect on NIH 3T3 cell viability after being reacted with bFGF-HDC@Fe₃O₄ nanoparticles at various conditions that may be encountered during preparation, storage, or application (e.g., 4 °C, 55 °C, pH 5.0, 1% trypsin, and 1% trifluoroacetic acid) [25]. The cell growth rate was much higher in the bFGF-HDC@Fe₃O₄ group than in the free bFGF group, particularly under harsh conditions, demonstrating that HDC@Fe₃O₄ was capable of effectively maintaining the stability of bFGF [25]. These nanoparticles also demonstrated good stability and controlled release, gradually releasing 40% of the bFGF and retaining 70% protein activity over 12 days [25]. Moreover, with the help of an external magnetic field, bFGF-HDC@Fe₃O₄ nanoparticles were efficiently distributed to the mitochondria of macrophages, thus, promoting anti-inflammatory phenotype macrophage polarization to accelerate tissue regeneration [25]. In 2020, Khosravi et al. developed curcumin-loaded superparamagnetic iron oxide nanoparticles (SPIONs) to treat testes damage caused by heat stress [33]. In another study, ferucarbotran, a commercial agent composed of SPIONs, was used to deliver bone marrow mesenchymal stem cells (MSCs) for the repairment of resected bladder tissue [34]. Using this method, the MSCs acquired magnetic characteristics allowing their accumulation in damaged areas under the direction of an external magnetic field, effectively enhancing tissue regeneration in a minimally invasive approach [34].

Mesoporous glass (e.g., borates, silicates, and phosphates) nanoparticles have been studied as carriers for regenerative medicine owing to their remarkable physicochemical properties, including ease of synthesis and functionalization, low mass density, controllable nanoparticle size, tunable microstructure, high specific surface area, and cytocompatibility [35]. In 2020, Hamam et al. developed curcumin-loaded mesoporous silica particles for tissue regeneration [36]. In another example, ultrasmall ceria nanocrystals with controlled reactive oxygen species (ROS) scavenging capability were loaded on uniform mesoporous silica nanoparticles to alleviate oxidative damage at the injury site [37]. These ceria-loaded nanoparticles induced regenerative healing effects, indicating their great potential for wound repair applications in which ROS-scavenging activity is beneficial [37]. In addition, Wang et al. developed poly(amidoamine) dendrimers modified mesoporous silica nanoparticles with controlled drug release properties for bladder cancer therapy [38]. This delivery system showed excellent mucoadhesive capabilities on bladder wall, which could provide enlightenment for the development of bioactive agent-based delivery systems for bladder regenerative treatment.

2.2. Organic Biomaterials

Organic biomaterials can be divided into synthetic polymeric and bioderived materials, depending on their source. Polymeric materials that are accurately synthesized through reproducible industrial processes have been widely utilized in regenerative medicine applications because of their tunable physicochemical properties ^[39][40][39,40]. In addition, these materials are popular for the sustained or controlled release of encapsulated active substances. Thus, polymeric materials, such as polylactide-co-glycolide (PLGA), polyethylene glycol (PEG), polyvinyl alcohol (PVA), and poly (ester amide) (PEA) are suitable candidates for carriers of bioactive agents in tissue regeneration. The possible release mechanisms of bioactive agents from synthetic polymers include time and condition-dependent surface erosion, desorption, and swelling and diffusion [14]. PLGA, which possesses a tunable degradation rate and induces minimal systemic cytotoxicity, is an attractive FDA-approved polyester in applications that require long-term delivery of therapeutic substances. Ciardulli et al. encapsulated human growth differentiation factor 5 in a PLGA nanocarrier for controlled delivery, thus, promoting tissue regeneration events [41]. PEG is another polyester that has received significant attention for its tunable geometry and hydrophilicity. Recently, Sok et al. developed a PEG-based hydrogel that showed promising results for delivery of aspirin-triggered resolvin D1 and recombinant human interleukin 10, resulting in recruitment of immune cells, their polarization towards pro-regenerative phenotypes, and subsequent healing of trauma wounds [42]. Liang et al. fabricated PEG—poly (ε-caprolactone-co-lactide)-based thermosensitive delivery system to deliver adipose stem cell-derived exosomes under sustained manner in corpus cavernous, and finally ended with erectile function restored [22]. PVA is a food and drug administration (FDA) approved polyol that can acquire ROS-responsive capacity after reacting with benzoboric acid [43]. Li et al. developed a hydrogel composed of PVA and benzoboric acid to deliver bFGF, demonstrating promising results for the repair of tissues with high ROS microenvironments [43]. PEA, a cationic polymer consisting of ester and amino groups synthesized from natural active biomolecules, is nontoxic and possesses excellent biodegradability, biocompatibility, and mechanical properties [44]. Yuan et al. recently synthesized PEA using L-arginine, L-phenylalanine, and inositol as raw materials [44]. Vitamin E encapsulated in PEA showed excellent antioxidative and anti-inflammatory properties in tissue engineering applications [44]. In 2020, PEA-plasmid polyplex-based delivery systems were used successfully to deliver exogenous deoxyribonucleic acid to the vagina/cervix without diffusing to nearby organs, which showed it immense application potential in vagina/cervix regenerative therapies [45]. Bioderived materials are defined as macromolecules extracted from microorganisms, animals, or plants ^[46][47][48][46,47,48]. Advantages such as high availability, biocompatibility, and bioactivity have facilitated the use of bioderived materials as delivery systems for therapeutic substance release and tissue repair ^[49][50][49,50]. Among them, proteins (including, fibroin, collagen, and keratin), polysaccharides (such as, glycosaminoglycans, alginate, chitosan, plant origin natural gum, cellulose, and gellan gum), lipids (such as liposomes and saturated fatty acids), extracellular vesicles (EVs), and extracellular matrix (ECM) have been extensively investigated and are reviewed in detail elsewhere ^{[51][52][53][54][55][56][57][58][59]}[51,52,53,54,55,56,57,58,59].