While the in vivo biocompatibility and efficacy of regenerative biomaterials are typically assessed using a subcutaneous (SC) implantation model, the profound impact of the implantation site's microenvironment is often overlooked, hindering the translational medicine of some new biomaterials. Here, we report that the injection location of a thermosensitive poly(D,L-lactide-co-glycolide)-poly(ethylene glycol)-poly(D,L-lactide-co-glycolide) hydrogel (T-gel) dictates tissue regeneration by spatiotemporally modulating local lactate accumulation and immune response in rats. Compared to SC injection, intradermal (ID) injection of T-gel significantly enhanced collagen generation, driven by a denser tissue architecture and more abundant stromal components. The compact ID niche intensified early cell–material interactions, triggering the release of damage-associated molecular patterns that activated resident macrophages via the TLRs–MyD88–NF-κB pathway, leading to amplified macrophage recruitment. Notably, T-gel underwent accelerated degradation in ID tissue, elevating local lactate levels, which concurrently promoted M2 macrophage polarization and directly stimulated fibroblast-mediated collagen biosynthesis. Our findings challenge the sole reliance on SC models for evaluating biomaterial efficacy and establish implantation site selection as a critical, yet underutilized, issue in regenerative strategy. This study highlights that the assessment of biomaterials for dermal regeneration and aesthetic applications must distinguish between ID and SC microenvironments, as they dictate different regenerative outcomes through distinct immunometabolic mechanisms.

Embolic microspheres are important for the interventional treatment of solid tumors, but it is a dilemma for microspheres to keep sufficient strength and resilience. Herein, we propose a strategy to fabricate core-shell poly(vinyl alcohol) microspheres with gradient crosslinking (GCL) on an industrial scale to solve the dilemma. The synthesized GCL microspheres exhibit superior mechanical characteristics in comparison to the homogeneous microspheres and the conventional core-shell microspheres produced by standard one-step and two-step methods, respectively. An in vitro model is conducted to assess the distribution in the vascular network and migration over time of three microspheres. The GCL microspheres possess optimal strength and flexibility, facilitating distal vascular embolization and reducing the risk of microsphere migration over time. The performances are validated in vivo with the porcine renal model in large animal experiments. Clinical trials addressing liver cancer further confirm the embolic efficacy and safety of the GCL microspheres in humans. The relationship between mechanical properties and embolic efficiency offers valuable insights for the development of other embolic agents in the formulism of interventional therapy.

Polymeric materials are difficult to be theoretically designed in silico because the synthesis reaction spans vast spatiotemporal scales from quantum-level reaction, chain growth and diffusion to engineering-level production, and the condensed state is determined via hierarchical self-assembly. Here, we report a “4+1” strategy that combines four independent computational methods (density functional theory, kinetic Monte Carlo simulation, dynamic Monte Carlo simulation, and flowsheet synthesis) with one mapping experiment to realize a multiscale engineering study of a complex polymer system. Integration is achieved through a feedback-loop mapping experiment, which bridges calculated energy barriers (quantum chemistry) with polymerization kinetics (statistical physics), and a coarse-grained model that transforms realistic polymer chains into operable ones. Studying the polymerization of amphiphilic poly(lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(lactide-co-glycolide) with the method reveals distinct kinetic stages across 24 basic reactions (12 for ring-opening polymerization and 12 for ester exchange) spanning 19 temporal and 12 spatial scales. Both simulations and experiments show that the amphiphilic polymer products collected at different time points display varied yet controlled condensed states in water, such as sol, precipitate, and heating-induced physical hydrogel (thermogel) even at similar number-average molecular weights. Additionally, thermogellability is predicted with artificial intelligence. Our study, conducted using a personal computer, establishes a fundamental methodology of ab initio molecular engineering of valuable polymers available for industrial-scale synthesis.

Rationale: The emergence of glucagon-like peptide-1 receptor agonists (GLP-1RAs) has advanced diabetes management. Nevertheless, frequent administration remains a challenge, even with weekly formulations. Herein, we developed a sustained-release hydrogel-based delivery system for Efsubaglutide Alfa (Suba), an IgG-conjugated GLP-1RA, designed to alleviate treatment burden and enhance patient adherence. Methods: A series of biodegradable poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymers were synthesized, and a thermosensitive PLGA-PEG-PLGA hydrogel with suitable sol-gel transition temperature and in vivo degradation profile was selected for the fabrication of the Suba-loaded hydrogel system (Suba@T-gel). The pharmacokinetic and pharmacodynamic profiles following subcutaneous administration of Suba@T-gel were evaluated in multiple rodent models. Results: In vivo non-invasive imaging and pharmacokinetic studies showed that a single subcutaneous injection of Suba@T-gel enabled sustained release of Suba for over three weeks. This prolonged release profile is attributed to moderate Suba-polymer interactions and the large molecular size of Suba, which facilitate sustained drug release through a carrier degradation-controlled mechanism. In diabetic murine models, a single administration of Suba@T-gel achieved stable glycemic control for three weeks. Furthermore, the continuous liberation of Suba remarkably enhanced insulin secretion, reduced glycosylated hemoglobin levels, and improved pancreatic function in diabetic mice. Additionally, this system ameliorated diabetes-related complications by improving lipid metabolism, reversing hepatic steatosis and enhancing nerve fiber density. Conclusions: The Suba@T-gel system represents a promising strategy for long-acting management of diabetes and substantial improvement in patient compliance.

Intervertebral disc degeneration (IVDD), frequently accompanied by low back pain, is a global public health challenge. Current therapeutic approaches are unable to halt IVDD progression due to their limited efficacy in promoting extracellular matrix (ECM) remodeling and suppressing inflammatory cascades. To address these issues, we develop an injectable hydrogel-based thermotherapy platform incorporating mesoporous polydopamine (mPDA) nanoparticles (NPs), termed mPDA@Gel. The introduction of mPDA NPs confers dual therapeutic benefits-efficient photothermal conversion and potent reactive oxygen species scavenging, while the prolonged retention of hydrogel matrix within the intervertebral disc (IVD) enables repeated thermotherapy interventions and exerts sustained anti-inflammatory effects following a single injection of mPDA@Gel. In vitro studies demonstrate that multiple mild thermotherapies combined with mPDA NP administration effectively restore ECM metabolic homeostasis in lipopolysaccharide-stimulated nucleus pulposus cells (NPCs) by modulating inflammatory signaling pathways. In vivo evaluation using a rat model of IVDD reveals that a single IVD administration of mPDA@Gel followed by multiple mild thermotherapy cycles significantly reduces disc height loss, minimizes ECM degradation, alleviates inflammatory responses, inhibits NPC apoptosis, relieves non-specific pain, and preserves biomechanical functions. These findings suggest that the proposed system offers a promising minimally invasive therapeutic strategy for the management of degenerative musculoskeletal diseases.

Cell migration is a basic biological process essential for physiological homeostasis and disease pathogenesis. It is interesting that random migration of a cell on an extracellular matrix or a biomaterial obeys the diffusion equation of Brownian particles proposed by Einstein in 1905, from which diffusivity can be used to quantify the migration rate. While the complexity of density dependence of diffusivity has been pointed out for cells, a function simply relating migration rate to cell density has never been reported. Herein we show that, unlike the diffusion of an abiotic particle, the migration rate of a living cell changes with cell density nonmonotonically, and a quantitative relation between migration rate and cell density is established by us, resulting in a product equation. The term dmax, namely, cell density for the fastest migration, is further defined and justified based on both real-time observations of cells and Monte Carlo simulations of model "living particles". The maximum migration rate is interpreted by the combination of volume-exclusion and autocrine effects, representing physical and biological effects, respectively. The regulation works universally across different cell types, culture media, and biomaterial surfaces examined by us, while the concrete values of dmax depend on these conditions. This fundamental study is helpful for understanding dynamic cell behaviors under material microenvironments and for the design of advanced biomaterials for tissue regeneration or drug carriers.

Periodontitis is a prevalent chronic inflammatory disorder characterized by progressive destruction of periodontal tissues, particularly irreversible alveolar bone resorption. Excessive generation of reactive oxygen species (ROS) plays a pivotal role in disease progression. Consequently, neutralizing ROS to quell inflammation while stimulating bone regeneration represents a promising strategy for periodontitis management. In this study, a multifunctional composite hydrogel system (MnNS@NO-Gel) was developed by integrating manganese dioxide nanosheets (MnNS) with robust ROS-scavenging capacity into a novel thermosensitive hydrogel capable of sustained nitric oxide (NO) release. This composite system exhibits a thermally induced sol-gel transition, forming a semi-solid hydrogel at body temperature that facilitates easy administration and provides prolonged structural retention following local injection into periodontal tissues. This platform enables the sustained co-delivery of MnNS and NO, effectively scavenging excess ROS, promoting macrophage polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype, and enhancing both osteogenic differentiation and vascularization. In vivo studies demonstrate that MnNS@NO-Gel significantly restores periodontal tissue structure, stimulates alveolar bone regeneration, and downregulates the expression of inflammatory markers. These findings indicate that the MnNS@NO-Gel system presents a promising therapeutic approach for periodontitis treatment by integrating anti-inflammatory, antioxidant, and regenerative functions to achieve restoration of damaged periodontal tissues.

A key yet often overlooked factor in the unpredictable failure of degradable systems is “acquired”; heterogeneity—a spatially and temporally evolving unevenness of degradation that emerges and aggravates during service, rather than originating from manufacturing defects. Controlling this inherent randomness is particularly critical for biodegradable implants, where corrodible metals offer the necessary strength but are susceptible to such unpredictable localized weakness throughout the therapeutic window. Herein, we propose that the reliability of a biodegradable device is highly dependent upon the extent of such “acquired”; heterogeneity. We derive an equation set of random degradation inspired by the Poisson raindrop question, and employ them to quantify the acquired heterogeneity of biometals with and without polymer coatings. We find that coating iron with polylactide increases the corrosion rate by 3-fold but reduces the inhomogeneity by 4,000-fold in a blood-mimetic medium, surprisingly leading to later device fracture despite faster degradation. The resulting biodegradation-controlled metal-polymer composite stents for interventional treatment prevent high-risk early and random fractures. Preclinical studies in pigs, clinical trials involving 1108 patients across multiple cohorts, and 5-year outcomes of 45 first-in-human implantations illustrate that the biodegradation-controlled metal-polymer composite stents are safe, durable, and reliable. Our theoretical framework is relevant to any discipline in which random tempospatial variability undermines system performance.

Thermosensitive hydrogels derived from thermogelling polymers have garnered growing interest as injectable biomaterials. However, conventional thermosensitive hydrogels often suffer from inadequate mechanical robustness and limited in vivo persistence. To address these issues, a series of amphiphilic poly(2-ethyl-2-oxazoline)-poly(L-alanine) (PEOz-PAla) copolymers are synthesized, and an injectable thermosensitive hydrogel based on thermogelling PEOz-PAla polymers is developed. By controlling the PEOz/PAla block ratio and polymer concentration, the sol-gel transition temperature and mechanical strength of the resulting hydrogel can be conveniently regulated. Multi-technique analyses indicate that the gelation mechanism involves thermally induced micelle aggregation, while the PAla domains possess pre-existing β-sheet-rich structures that substantially boost the hydrogel's mechanical performance. UV irradiation effectively sterilizes the PEOz-PAla powder, and pre-filled hydrogels display good storage stability at ambient temperature for more than three months. Non-invasive fluorescence imaging combined with traditional anatomical observation reveals that the PEOz-PAla hydrogel degrades stably and gradually at the subcutaneous injection site over 100 days, with biocompatibility confirmed by in vitro cytocompatibility and in vivo histological assessments. Furthermore, real-time fluorescence tracking verifies the sustained release of encapsulated macromolecular drugs for over 35 days. These results establish the PEOz-PAla hydrogel as a promising platform for sustained drug delivery and tissue engineering applications. STATEMENT OF SIGNIFICANCE: In this study, we developed a new thermosensitive and injectable hydrogel using rationally engineered poly(2-ethyl-2-oxazoline)-poly(L-alanine) (PEOz-PAla) copolymers. Compared with previously reported thermosensitive hydrogels, this hydrogel system simultaneously achieves enhanced mechanical properties and prolonged in vivo retention (> 100 days). Meanwhile, by systematically tuning the block lengths of PEOz and PAla, as well as the polymer concentration, a structure-property relationship is also established for thermogelling PEOz-PAla copolymers. Overall, this study introduces a design strategy for the development of new thermogelling polymers.

The function of a biomaterial has been expected from simply providing a passive structural support to actively modulating biological responses covering many aspects including but not limited to treatments of neurodegenerative disorders. This article reviews the advances of various biomedical materials relevant to treatments of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. These progressive diseases pose multifaceted challenges, including the limited regenerative capacity and the formidable blood–brain barrier (BBB). The review introduces the interdisciplinary progress of brain-targeted biomaterials, encompassing synthetic polymers, biologically derived carriers, and inorganic nanoparticles, with particular attention to their roles in overcoming BBB penetration and enabling precise drug delivery. In parallel, we discuss neuroprotective and regenerative biomaterials that promote extracellular matrix (ECM) remodeling, enhance neuronal survival, and guide neural regeneration. In addition, biomaterials are being integral to the next generation of brain–machine interfaces or brain–computer interfaces, where the materials are used to improve device biocompatibility and long-term stability. The review also covers advances in deep brain stimulation and implantable neuro-prostheses for functional restoration of neurodegenerative disorders. Finally, we propose perspectives: ① integration of stimuli-responsive materials with biological carriers for precise and targeted drug delivery; ② prioritization of material–tissue interactions to enhance the safety and functionality of neuro-devices; ③ biomimetic design of ECM-inspired materials with neuroprotective and regenerative capacities; ④ investigation of dynamic interfaces between brain tissue and external implants to improve long-term performance of medical devices; and ⑤ convergence of artificial intelligence, organ-on-chip platforms, and biomaterials to accelerate translational research.

Surface endothelialization of a medical device after implantation into the cardiovascular system depends upon competitive migration between endothelial cells (ECs) and smooth muscle cells (SMCs). While both cell types have been extensively studied, the relative migration under mixed co-culture conditions remains elusive. Herein, we investigate the migration of ECs and SMCs on tissue culture plates under different culture modes. Compared with monocultures, mixed co-culture slows down the migration of both cell types. Our analyses suggest that this reduced migration likely involves intensified intercellular interactions and expanded cell coverage during the mixing of two entities with different sizes. We find that the mixed co-culture may alter the relative migration between ECs and SMCs. We further examine the relative migration of the two cell types on arginine-glycine-aspartate (RGD) nanoarrays prepared using block copolymer micelle nanolithography and show that nanopatterns with varied RGD nanospacings (29-121 nm) can significantly tune the relative migration rate, effectively reversing the migratory dominance of one cell type over the other. This study sheds new insights on the behavior of co-cultured cells on biomaterials with modified surfaces.

Biodegradable polymeric excipients are fundamental to drug delivery systems (DDSs) governing the kinetics of drug release. Encapsulated hydrophobic drugs have the potential to reciprocally shape the in vivo fate of amphiphilic carriers. However, quantifying this interplay and the carrier's own absorption, distribution, metabolism, and excretion (ADME) has been hindered by technical difficulties arising from the polydispersity of synthetic polymers. Herein, we proposed reduced-dimensional mass spectrometry (RDMS) to enable direct, label-free tracking of intact polydispersed polymers, demonstrated by the thermogelling block copolymer composed of poly(lactide-co-glycolide) (PLGA) and poly(ethylene glycol) (PEG). By detection of polymer concentrations in the plasma and other tissues after subcutaneous (s.c.) injection, we found that the hydrophobic antitumor drug irinotecan (IRN) significantly delayed the carrier's systemic absorption and dictated its metabolic fate, wherein the copolymer underwent rapid hydrolysis to PEG, which was predominantly distributed to the kidneys and excreted renally. This work establishes a dynamic feedback loop of bidirectional pharmacokinetics (PK) and provides the first comprehensive ADME profile of this intelligent self-assembling amphiphilic block copolymer, an International Union of Pure and Applied Chemistry (IUPAC) Top 10 Emerging Technology in 2025.

Iron-based biodegradable stents hold significant promise for percutaneous coronary intervention. Our previous study has revealed that a polylactide (PLA) coating can not only accelerate iron corrosion but also mitigate corrosion inhomogeneity, presenting a metal-polymer composite stent (MPS). Nevertheless, current understanding of how PLA coating parameters regulate iron corrosion remains limited. This article represents the systematic and quantitative in vitro investigation into the effects of coating thickness, molecular weight, and end group of PLA on the corrosion rate and inhomogeneity of an iron substrate under biomimetic conditions. By theoretically developing an equation set to quantify random degradation with time-dependent inhomogeneity and experimentally combining immersion corrosion tests with electrochemical analysis, we elucidate the spatiotemporal evolution of iron corrosion under different coating parameters. Our findings provide a crucial foundation for optimizing the degradation behavior of MPS and stimulating the design of other biodegradable materials.

Wear particle-induced prosthesis aseptic loosening severely affects the longevity of total joint arthroplasty. This condition arises from periprosthetic osteolysis, which is driven by excessive inflammation and enhanced bone resorption under particle stimulation. Herein, we develop an injectable hydrogel-based system co-encapsulating anti-inflammatory emodin (Emo) and anti-osteoporotic salmon calcitonin (sCT) to synergistically inhibit wear particle-induced aseptic loosening. This hydrogel is formulated from thermosensitive poly(lactic acid-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(lactic acid-co-glycolic acid) triblock copolymers and water. The aqueous system undergoes a sol-to-gel phase transition upon heating with the transition temperature between room temperature and body temperature. Highly hydrophobic Emo is efficiently solubilized into micelles formed by the amphiphilic carrier polymers, while hydrophilic sCT is encapsulated within bovine serum albumin (BSA)-derived nanoparticles to suppress its initial burst release and prolong its release duration from the hydrogel matrix. This dual-delivery platform achieves simultaneous and continuous liberation of both therapeutic agents with distinct properties. In a mouse bone-implanted air pouch model, a single administration of the hydrogel formulation plus the sustained release of active Emo and sCT efficiently suppresses titanium particle-induced aseptic inflammation and osteolysis. Therefore, this local and long-acting co-delivery system holds great promise for preventing wear particle-induced aseptic loosening.

Thrombus on implants is dangerous, necessitating anticoagulant coatings for most of blood-contacting devices with various substances. So far, there is no universal strategy of the pertinent surface modification for different substrates, which significantly hinders the efficient research and development of blood-contacting medical devices. Herein, we propose a modular strategy to construct anticoagulant coatings on substrates including polymers, metals and nonmetallic inorganics. Inspired by the principle of primary antibody and secondary antibody in biological immunoassay, we develop a universal two-module modification approach: firstly surface activation of various substrates to generate charged surfaces with specific reactive functional groups, and secondly linking the anticoagulating moieties to the substrate via the functional groups. The feasibility of surface activation like linking the primary antibody is confirmed using 12 substrates; the final coatings analogous to linking the secondary antibody are demonstrated using a biopassive coating with 2-methacryloyloxyethyl phosphorylcholine polymer and a bioactive coating with heparin. The anticoagulant efficacy of the biopassive coating is accessed in extracorporeal circulation devices, and that of the bioactive coating in cerebral embolic protection devices minimally invasively implanted into heart through catheter. Both coatings prepared with our modular strategy have been verified in vitro and in large animals (sheep or pig).

Epithelial-mesenchymal transition (EMT) is a key phenotypic switch in cancer metastasis, leading to fatal consequences for patients. Under geometric constraints, the morphology of cancer cells changes in both cellular and subcellular levels, whose effects on EMT are, however, not fully understood. Herein, we designed and fabricated chimeric micropatterns of polystyrene (PS) with adhesion contrast to reveal the impacts of cell shapes and nuclear shapes on EMT in a decoupled way. Cell elongation was modulated via microwell aspect ratios (ARs), and nuclear deformation was generated through a micropillar array in the microwell. Human non-small cell lung cancer cells (A549) were cultured on the quasi-three dimensional micropatterned surfaces, and transforming growth factor-β1 (TGF-β1) was added to induce EMT. We found that chimeric micropatterns upregulated EMT with an increase of cellular AR and nuclear indentation under given TGF-β1. The subsequent assessment of the contractility and oriented assembly of microfilaments elucidated the key role of mechanotransduction in cell elongation and EMT, as proved by myosin inhibition, while it was obstructed by micropillars in the chimeric micropattern. Hence, the micropillar array possessed a nonmonotonic influence, enhancing the EMT of cells with AR of 1, but hindering the EMT with an impact more significant on microwells with large ARs due to the impeded cytoskeleton assembly. This fundamental research has illustrated the complex of cellular and subcellular geometries on cell behaviors including phenotype transition in cancer metastasis.

Cells respond to adhesive ligands such as arginine-glycine-aspartate (RGD) through integrins, which regulates cellular activities via influencing cytoskeleton assembly. Herein, we report that the nanoscale distribution of active ligands on biomaterials regulates cells through not only cytoplasmic tension but also nuclear tension. This is particularly related to translocation of actin into nucleus and highlighted in our interpretation of an "abnormal" phenomenon that large RGD nanospacing (>70 nm) disassembles integrin clusters, inhibits cell adhesion, but promotes osteogenic differentiation of mesenchymal stem cells. Our studies reveal that the unstable adhesion at the 150 nm RGD distance increases actin dynamics, resulting in the nuclear translocation of globular (G) actin. The compartment polymerization of more G-actins to filamentous actins in nucleus increases nuclear tension, facilitating transcription activity and releasing calcium ions from the endoplasmic reticulum. This noncanonical mechanotransduction process sheds insight into mechanotransduction pertinent to cell-material interactions.

Recent advancements in biomaterials have profoundly transformed the fields of dermatology and tissue engineering, etc., offering innovative solutions that markedly improve skin treatment outcomes. This review provides a comprehensive overview of the latest developments in natural, synthetic, and composite biomaterials tailored for skin treatments and skin-related medical devices, including wound healing, tissue engineering, drug delivery, dermatological therapies, medical aesthetics, e-skin, and skin-related surgery-assistant devices. The incorporation of artificial intelligence (AI) into biomaterial design has facilitated the development of adaptive and predictive systems capable of responding dynamically to the skin's physiological needs. Moreover, an in-depth understanding of the interactions between biomaterials and cells, as well as the activation of biological pathways and regulation of cellular processes is pivotal for enhancing skin health and function. Looking forward, the main efforts toward future in this field are suggested as follows: 1) Development of novel materials remains central; 2) Responsive biomaterials enable precise therapy; 3) Integration with cell therapy is pivotal in regenerative medicine; 4) In-depth investigations into material-driven biological mechanisms are critical for innovative design of skin-related materials; 5) Interdisciplinary collaboration is vital for the rapid evolution of biomaterials; 6) Enhanced applications of AI is driving the development of adaptive and predictive biomaterials.

The field of orthopaedic implants has experienced rapid growth in recent decades, evolving from a few obscure examples to become one of the most vibrant domains within regenerative medicine. Polyetheretherketone (PEEK) stands out as a formidable competitor in this field due to its exceptional biocompatibility and appropriate mechanical strength. However, the clinical application of PEEK is limited by its inherent biological inertness. Therefore, numerous studies have focused on overcoming the bio-inert issue of PEEK using surface activation techniques. It is necessary to delve into the intricate effects of these modifications and their corresponding methods. In this review, we provide a comprehensive summary of contemporary research on surface modification for enhancing osseointegration of PEEK implants, categorising them into four parts based on their modification methods and techniques used: (1) physical treatment, (2) wet chemical methods, (3) combination of physical and chemical treatments, and (4) bioactive coating. Finally, we outline the challenges and unmet needs that must be addressed by future designs of PEEK surfaces. Overall, altering the surface morphology and/or surface group of PEEK to obtain a rough, porous, hydrophilic, and bioactive surface, or incorporating bioactive agents/coatings with bone-forming abilities onto the surface of PEEK has shown great potential for promoting osseointegration, which can serve as a solid foundation for subsequent clinical translation.

Poly(lactic acid) (PLA), a bioplastic currently with the highest production capacity, represents a promising alternative to traditional petroleum-based plastics. However, its slow degradation in natural environments and limited recycling options restrict its large-scale application. We recently discovered that diphenyl phosphate (DPP) can serve as a catalyst for PLA hydrolysis. Herein, to screen a more potent catalyst for PLA hydrolysis, various DPP derivatives are synthesized. We reveal that the catalytic degradation of PLA follows a dual activation mechanism, and the catalytic activity of these derivatives correlates positively with the electron deficiency of aromatic substituents. p-Bis-nitrophenyl phosphate (p-BNPP) with the strongest electron-withdrawing groups demonstrates the highest catalytic performance for PLA hydrolysis reported to date. Using just 3.5 wt% p-BNPP and a small amount of water, commercial PLA pellets/products are efficiently hydrolyzed into oligo(lactic acid) (OLA) with the average degree of polymerization below 4 within 30 min at 160 degrees C, without external pressure or organic solvents. p-BNPP can be reused at least 10 times and works well for other biodegradable polyester/polycarbonate hydrolysis. The resulting OLA can either be repurposed for producing high-quality PLA or transformed into a concentrated lactic acid solution. Additionally, this recycling flowsheet is successfully implemented in a kilogram-scale batch reactor.