The synergistic effects of VEGF and PDGF in PRP play pivotal roles in stimulating endothelial cell proliferation and migration, with VEGF directly promoting these processes and facilitating microcirculation reconstruction through the activation of the vascular endothelial growth factor A (VEGFA)/vascular endothelial growth factor receptor 2 (VEGFR2) pathway, as evidenced in models of diabetic foot ulcers [6], while also enhancing capillary formation and blood flow restoration in ischemic tissues by upregulating MMP2/9 and Estrogen Receptor Alpha (ER$\alpha$)/Rho-associated, coiled-coil containing protein kinase 2 (ROCK2) signaling pathways [7]. PDGF, on the other hand, promotes cell migration and adhesion through Protein Kinase B (AKT) activation within the integrin signaling pathway, exhibiting superior effects compared to PDGF-BB alone, and its receptor, platelet-derived growth factor receptor beta (PDGFR$\beta$), regulates pericyte survival and migration, thereby stabilizing newly formed blood vessels [8]. Additionally, TGF-$\beta$, stored in a latent form within the extracellular matrix (ECM), modulates ECM deposition and fibrosis repair upon activation through the TGF-$\beta$1/SMAD2/3 pathway [9]. In the context of MI, VEGF-C enhances post-MI angiogenesis by promoting clonal expansion of coronary endothelial cells, while PDGF-BB and TGF-$\beta$1 contribute to the stabilization of the neovascular network by regulating ECM remodeling and pericyte coverage [10]. Collectively, these growth factors drive neovascularization, improving blood perfusion to ischemic tissues, particularly beneficial for patients with peripheral artery disease or myocardial infarction [11].

PRP demonstrates remarkable anti-inflammatory and immunomodulatory capabilities rooted in its complex cytokine and growth factor composition [12, 13, 14]. By releasing anti-inflammatory mediators like interleukin-10 (IL-10) and TGF-$\beta$ while suppressing pro-inflammatory cytokines such as tumor necrosis factor-$\alpha$ (TNF-$\alpha$) and interleukin-6 (IL-6), PRP effectively balances inflammatory responses. Additionally, its growth factors including VEGF, PDGF, and TGF-$\beta$—not only drive tissue repair but also indirectly reduce inflammation by accelerating healing processes. This dual action is further enhanced through reactive oxygen species scavenging and modulation of immune cell phenotypes, such as shifting macrophages from M1 to M2 and regulating T-cell responses to prevent excessive immune activation [15]. In inflammatory diseases such as osteoarthritis, PRP demonstrates therapeutic effects through its dual actions, not only alleviating pain (associated with reduced levels of TNF-$\alpha$ and IL-6) [16, 17, 18] but also promoting tissue repair. A study has further revealed that leukocyte-rich PRP (LR-PRP) exhibits stronger anti-inflammatory properties compared to leukocyte-poor PRP (LP-PRP), as evidenced by higher levels of IL-1 and IL-4 [19]. Collectively, these findings suggest that PRP restores inflammatory balance through a “bidirectional regulatory” mechanism—simultaneously enhancing anti-inflammatory effects and suppressing pro-inflammatory responses [20]. This characteristic endows PRP with potential applications in the treatment of various inflammation-related diseases [21].

PRP’s therapeutic potential shines in cardiovascular pathologies where inflammation and immune dysregulation are pivotal. In conditions like atherosclerosis, myocardial infarction, and peripheral artery disease, PRP limits plaque inflammation, reduces infarct size, and promotes neovascularization in ischemic tissues [22]. However, its efficacy hinges on formulation nuances—such as leukocyte content—and delivery methods, which influence cytokine bioavailability and immune cell trafficking.

By activating resident cardiac progenitor cells and enhancing cardiomyocyte survival, PRP promotes myofiber alignment and improves contractile function in infarcted hearts. Preclinical studies demonstrate that PRP therapy increases left ventricular ejection fraction (LVEF) and holds promise for structural and functional restoration of damaged myocardium [23, 24].

Research indicates that PRP may enhance myocardial repair through novel mechanisms, such as Piezo1 channel activation [4]. Piezo1, a mechanically sensitive cation channel, facilitates an increase in intracellular Ca²⁺ levels [25]. PRP activates the AKT pathway within the integrin signaling cascade via PDGF receptor tyrosine kinase, thereby promoting the adhesion and migration of cardiac progenitor cells (CPCs) [26]. Concurrently, the mechanically sensitive ion channel Piezo1, upon sensing mechanical stimuli in CPCs, mediates calcium influx, enhancing their proliferative and differentiative capabilities through the Ca²⁺/Hypoxia-inducible factor 1$\alpha$ (HIF-1$\alpha$)/VEGF signaling axis [27], and modulates paracrine functions to facilitate myocardial repair [28]. In endothelial cells (ECs), the synergistic effects of VEGF and PDGF released by PRP are notable: VEGF activates the endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) and PI3K/AKT pathways by binding to VEGFR2 [29, 30], while PDGF enhances cell migration through an integrin-dependent mechanism. Together, they regulate Piezo1-mediated Ca²⁺ influx, dynamically balancing angiogenesis (via the HIF-1$\alpha$/VEGF and FGF2 pathways) [31] and endothelial permeability (modulated by VEGF-induced barrier function) [32]. In pathological microenvironments, hypoxia exacerbates VEGF secretion by upregulating Piezo1 and HIF-1$\alpha$ expression, whereas inflammation disrupts EC function through the ERK/p38/STAT1 signaling pathway [33]. However, the activation of the Piezo-type mechanosensitive ion channel component 1 - Calcium/calmodulin-dependent protein kinase II - Focal adhesion kinase/Proto-oncogene tyrosine-protein kinase Src - Yes-associated protein (Piezo1-CaMKII-FAK/Src-YAP) axis alleviates endothelial inflammation in atherosclerosis [34], underscoring PRP’s dual cell-specific mechanisms—promoting regeneration in CPCs via the PDGF-integrin-Piezo1 axis and coordinating vascular homeostasis in ECs [35].

PRP has emerged as a promising therapeutic option for ischemic heart disease, including conditions like angina and MI [36, 37]. By delivering a concentrated cocktail of growth factors such as PDGF-BB, TGF-$\beta$, and VEGF directly to ischemic myocardium, PRP activates endogenous repair mechanisms. This includes stimulation of cardiomyocyte proliferation, angiogenesis, and modulation of fibroblast activity to minimize scar formation [4, 36, 37, 38, 39].

In severe angina patients, PRP has shown good safety profiles while promoting myocardial repair through accelerated angiogenesis and mitigation of oxidative stress. The presence of anti-inflammatory cytokines in PRP also aids in reducing inflammation and apoptosis, further protecting cardiac tissue from ischemic injury. Additionally, PRP’s ability to reduce E-selectin expression improves endothelial function, which is crucial for cardiovascular health [40]. An experimental study has highlighted that PRP derived from young donors can rejuvenate aged bone marrow mesenchymal stem cells (BMSCs), enhancing their therapeutic efficacy in ischemic heart disease [41]. These findings underscore PRP’s potential as a dynamic therapeutic tool in addressing ischemic heart disease and its complications.

Emerging therapeutic strategies leveraging bioactive agents and bioengineered constructs have demonstrated promising outcomes in enhancing vascular regeneration and myocardial repair. A notable synergistic approach combines transmyocardial revascularization (TMR) with PRP to augment cardiac function post-coronary artery bypass grafting (CABG). This combinatorial therapy capitalizes on TMR’s mechanical creation of channels in ischemic myocardium and PRP’s pro-angiogenic growth factors, collectively improving myocardial perfusion and contractile function [42]. PRP has emerged as a versatile therapeutic with multi-faceted benefits. Clinical trials in patients with severe angina highlight its remarkable safety profile, while preclinical studies underscore its regenerative potential. For instance, PRP injection in MI patients significantly improves cardiac function and quality of life by stimulating neovascularization and inhibiting scar formation [43]. Additionally, PRP accelerates cardiac healing by mobilizing reparative cells and modulating inflammation [3].

In PAD, where arterial occlusion heightens amputation risks, bioengineered scaffolds incorporating mast cells (MCs) and PRP within chitosan matrices have demonstrated therapeutic angiogenesis. A rat hindlimb ischemia model revealed that MCs- and PRP-loaded scaffolds enhanced vascular density and restored blood flow, offering a promising strategy for ischemic tissue revascularization [44].

Collectively, these studies emphasize the translational potential of combinatorial therapies and bioengineered constructs in addressing cardiovascular pathologies. By harnessing the angiogenic and immunomodulatory properties of PRP, alongside stem cell mobilization strategies, clinicians may achieve superior outcomes in myocardial repair and peripheral vascular regeneration.

Beyond its regenerative and angiogenic properties, PRP demonstrates immunomodulatory capacities that mitigate post-injury inflammation. Leukocytes and growth factors within PRP coordinate an anti-inflammatory response to limit tissue damage. In inflammatory cardiovascular pathologies such as myocarditis and pericarditis, PRP suppresses pro-inflammatory cytokine release, alleviates clinical symptoms, and promotes tissue repair. Notably, PRP-derived leukocytes secrete anti-inflammatory cytokines like IL-10 while paracrine signaling inhibits pro-inflammatory mediators such as TNF-$\alpha$ and IL-6. This immunoregulatory mechanism provides distinct therapeutic benefits in inflammatory heart diseases. Preclinical studies of autoimmune myocarditis show PRP therapy reduces myocardial macrophage infiltration by 50% and decreases fibrotic regions by 35% via TGF-$\beta$/Smad signaling pathway downregulation [3]. Additionally, PRP’s immunomodulatory actions enhance transplanted stem cell survival and engraftment efficiency, fostering a synergistic environment for tissue restoration.

PRP exhibits therapeutic potential in cardiovascular regeneration by releasing bioactive molecules such as VEGF, PDGF, and TGF-$\beta$, which promote angiogenesis, inhibit inflammation, and enhance myocardial repair. Preclinical studies confirm its ability to improve blood perfusion in ischemic myocardium and accelerate postoperative wound healing [45, 46].

The side effects of PRP are generally mild and transient. However, it is crucial to remain vigilant about potential risks, which include: temporary redness, swelling, pain, or bruising at the local injection site; pathological reactions caused by an excess of growth factors, such as neointimal hyperplasia due to excessive VEGF stimulation leading to vascularproliferation (especially increasing the risk of restenosis in peripheral arterial disease), or PAD [58], or myocardial/tissue fibrosis induced by an overabundance of TGF-$\beta$ [59]; in extremely rare cases, it may activate systemic pro-inflammatory mediators (e.g., IL-1$\beta$) or trigger immune imbalance (e.g., high-leukocyte PRP activating M1 macrophages). Additionally, there is a risk of thrombosis due to the high activity of platelets, particularly in high-risk populations such as those with atrial fibrillation. Therefore, in clinical practice, it is essential to strictly adhere to the principles of individualized assessment and dynamic monitoring.

Current PRP formulations lack precise spatiotemporal control over bioactive molecule release, which is critical given the context-dependent actions of these factors. For example, while VEGF in PRP promotes angiogenesis in ischemic myocardium, its uncontrolled delivery risks disrupting vascular homeostasis. Similarly, the immunomodulatory effects of leukocytes in PRP are context-specific, aiding recovery in acute injury but potentially exacerbating chronic fibrosis. Furthermore, recent findings highlight the detrimental impact of persistently elevated growth differentiation factor 11 (GDF11) levels during aging [60], which may contribute to the loss of cardioprotective mechanisms and poor outcomes in elderly patients following acute myocardial infarction. These insights underscore the need for mechanism-specific biomarkers and targeted delivery strategies to optimize PRP’s therapeutic efficacy across diverse clinical scenarios.

While PRP’s therapeutic potential is evident, its clinical translation is hindered by methodological heterogeneity in preparation protocols. To address this, we propose adopting Food and Drug Administration (FDA)-like regulatory frameworks for PRP manufacturing, including: Define minimal platelet concentrations (e.g., $\ge$1 $\times$ 10⁹ platelets/µL) based on clinical trial data (e.g., ISTH guidelines) to ensure therapeutic efficacy. Stratify PRP formulations into LR-PRP vs. LP-PRP​ based on disease context (e.g., LR-PRP for acute inflammation, LP-PRP for chronic ischemia) to balance pro-/anti-inflammatory effects. Standardize agonists (calcium chloride vs. thrombin) and activation times to control growth factor release kinetics (e.g., sustained release via collagen scaffolds). These measures would align PRP production with Good Manufacturing Practice principles, enhancing inter-study comparability and regulatory approval pathways.

Preclinical studies often overlook fundamental differences between rodent and human cardiac biology. For example: Unlike rodents, adult human cardiomyocytes exhibit minimal regenerative capacity, rendering rodent models of PRP-induced LVEF improvement poorly predictive of human outcome. Rodent hearts require microliter volumes of PRP, whereas clinical translation demands milliliter-scale delivery with maintained bioactivity. Future studies must prioritize large-animal models (e.g., porcine MI) to bridge this gap and validate PRP’s efficacy in systems recapitulating human cardiac physiology.

PRP’s therapeutic value remains undefined relative to established interventions: While PRP enhances TMR-CABG outcomes, its combination with stem cell-TMR has not been evaluated for synergistic effects on myocardial regeneration. Autologous PRP is inexpensive compared to exosome-based therapies, but its short half-life (72 hours) may necessitate repeated injections, raising long-term costs. Health-economic analyses and head-to-head RCTs are urgently needed to define PRP’s niche in the regenerative therapeutics landscape.

The paucity of long-term data undermines confidence in PRP’s safety profile: Early studies report transient arrhythmias post-PRP injection, but $\ge$5-year risks of sustained arrhythmias or scar destabilization remain unexplored. While PRP reduces infarct size acutely, its impact on collagen cross-linking and diastolic dysfunction over decades is unknown. Registry studies tracking $\ge$10-year outcomes in PRP-treated cohorts are critical to validate durability and rule out delayed complications.

Current PRP protocols lack standardized stratification tools, such as baseline inflammatory biomarkers (e.g., high-sensitivity C-reactive protein, hs-CRP) and platelet function assays (e.g., VerifyNow® P2Y12), to identify responder populations. Elevated hs-CRP or TNF-$\alpha$ levels may predict adverse responses to leukocyte-rich PRP, necessitating leukocyte depletion in pro-inflammatory phenotypes. VerifyNow® P2Y12 testing can optimize platelet activation protocols by identifying patients with impaired platelet reactivity, while integrating multi-omics signatures (e.g., platelet RNA profiles) into clinical.

Nanotechnology is revolutionizing cardiovascular therapies by enhancing PRP efficacy through bioengineering. Nanoparticles serve as precision delivery vehicles for bioactive molecules in PRP, enabling targeted delivery to injured tissues. As detailed in Table 2, designing nanocarriers involves target identification, material selection, growth factor loading, and in vivo validation to optimize specificity, stability, and therapeutic outcomes. This approach minimizes off-target effects and maximizes regenerative potential.

Emerging studies, exemplified by Vilella-Figuerola et al. [61], underscore the necessity of characterizing platelet-derived extracellular vesicles across diverse cardiac pathologies, revealing nanotechnology’s potential to tailor PRP therapies to distinct clinical scenarios. While advanced nanomaterials integrate stimuli-responsive mechanisms (e.g., pH-sensitive linkages, magnetic guidance) to enhance delivery precision, current proposals inadequately address off-target risks such as pulmonary accumulation or immune activation. Similarly, CRISPR-edited exosomes—repurposed as nanocarriers for gene-silencing therapies—raise concerns about unintended genomic effects, including off-target editing in bystander cells or genomic instability, which remain unvalidated in preclinical models. These limitations necessitate rigorous evaluation of nanocarrier biocompatibility, CRISPR fidelity, and scalable delivery systems to bridge translational gaps in cardiovascular PRP applications.

While single-cell RNA sequencing (scRNA-seq) and AI offer transformative insights into PRP cellular heterogeneity and platelet subset functional specialization in cardiovascular disease, current applications overlook critical clinical variables such as patient comorbidities (e.g., diabetes-induced platelet hyperreactivity) and circulating factors (e.g., GDF11 modulating stem cell activity). Integrating platelet subpopulations (e.g., CD41+CD62P+ subsets linked to thrombotic vs. reparative phenotypes) with clinical outcomes (e.g., post-MI neointimal hyperplasia or diastolic dysfunction) is essential to refine predictive models. Without accounting for these confounders, AI-driven PRP personalization risks misclassifying high-risk cohorts, such as diabetic patients with GDF11-driven platelet dysfunction, underscoring the need for multi-omic integration to anchor therapeutic decisions in biological and clinical reality.

Standardizing PRP preparation is crucial for ensuring safety and efficacy. Microfluidic devices and closed-loop centrifugation systems (Table 3) minimize batch variability, ensuring consistent platelet counts and growth factor profiles. AI-powered sensors can monitor critical parameters, such as pH and temperature, in real-time during PRP processing. Automated quality control further guarantees that each batch meets therapeutic standards, reducing human error and variability.

Multidisciplinary collaboration among engineers, clinicians, and regulatory bodies is essential for advancing PRP therapies, with practical relevance enhanced by citing ongoing projects such as those integrating engineers in device design for closed-loop centrifugation systems with AI quality control, alongside clinicians optimizing dosage, as real-world examples of cross-disciplinary work. Establishing international standards for exosome characterization and adopting adaptive trial designs will accelerate clinical validation, while regulatory innovation is crucial to adapt to emerging technologies, ensuring patient access to safe and effective novel therapies. Such translational partnerships, bolstered by tangible collaborations and real-world applications, will bridge the gap from laboratory discovery to clinical application, accelerating the development of next-generation PRP-based treatments.