Protocol for embedded 3D printing of heart tissues using thiol-norbornene collagen.

Here, we present a protocol for 3D printing heart tissues using thiol-norbornene photoclick collagen (NorCol). We describe steps for synthesizing NorCol, preparing bioink and the support bath, and cell-laden printing. We then detail procedures for the loading of C2C12 cells into NorCol, ensuring structural integrity and cell viability after printing. This protocol is adaptable to various cell lines and allows for the printing of diverse complex structures, which can be used in drug screening and disease modeling.

Self-Reinforced MOF-Based Nanogel Alleviates Osteoarthritis by Long-Acting Drug Release.

Intra-articular injection of drugs is an effective strategy for osteoarthritis (OA) treatment. However, the complex microenvironment and limited joint space result in rapid clearance of drugs. Herein, a nanogel-based strategy is proposed for prolonged drug delivery and microenvironment remodeling. Nanogel is constructed through the functionalization of hyaluronic acid (HA) by amide reaction on the surface of Kartogenin (KGN)-loaded zeolitic imidazolate framework-8 (denoted as KZIF@HA). Leveraging the inherent hydrophilicity of HA, KZIF@HA spontaneously forms nanogels, ensuring extended drug release in the OA microenvironment. KZIF@HA exhibits sustained drug release over one month, with low leakage risk from the joint cavity compared to KZIF, enhanced cartilage penetration, and reparative effects on chondrocytes. Notably, KGN released from KZIF@HA serves to promote extracellular matrix (ECM) secretion for hyaline cartilage regeneration. Zn2+ release reverses OA progression by promoting M2 macrophage polarization to establish an anti-inflammatory microenvironment. Ultimately, KZIF@HA facilitates cartilage regeneration and OA alleviation within three months. Transcriptome sequencing validates that KZIF@HA stimulates the polarization of M2 macrophages and secretes IL-10 to inhibit the JNK and ERK pathways, promoting chondrocytes recovery and enhancing ECM remodeling. This pioneering nanogel system offers new therapeutic opportunities for sustained drug release, presenting a significant stride in OA treatment strategies.

In Situ Remodeling of Efferocytosis via Lesion-Localized Microspheres to Reverse Cartilage Senescence.

Efferocytosis, an intrinsic regulatory mechanism to eliminate apoptotic cells, will be suppressed due to the delayed apoptosis process in aging-related diseases, such as osteoarthritis (OA). In this study, cartilage lesion-localized hydrogel microspheres are developed to remodel the in situ efferocytosis to reverse cartilage senescence and recruit endogenous stem cells to accelerate cartilage repair. Specifically, aldehyde- and methacrylic anhydride (MA)-modified hyaluronic acid hydrogel microspheres (AHM), loaded with pro-apoptotic liposomes (liposomes encapsulating ABT263, A-Lipo) and PDGF-BB, namely A-Lipo/PAHM, are prepared by microfluidic and photo-cross-linking techniques. By a degraded porcine cartilage explant OA model, the in situ cartilage lesion location experiment illustrated that aldehyde-functionalized microspheres promote affinity for degraded cartilage. In vitro data showed that A-Lipo induced apoptosis of senescent chondrocytes (Sn-chondrocytes), which can then be phagocytosed by the efferocytosis of macrophages, and remodeling efferocytosis facilitated the protection of normal chondrocytes and maintained the chondrogenic differentiation capacity of MSCs. In vivo experiments confirmed that hydrogel microspheres localized to cartilage lesion reversed cartilage senescence and promoted cartilage repair in OA. It is believed this in situ efferocytosis remodeling strategy can be of great significance for tissue regeneration in aging-related diseases.

The Role of First Tarsometatarsal Joint Morphology and Instability in the Etiology of Hallux Valgus: A Case-Control Study.

BACKGROUND: The morphology of foot joints is widely accepted as a significant factor in the development of various foot disorders. Nevertheless, the role of the first tarsometatarsal joint (TMT1) morphology in hallux valgus (HV) remains unclear, and its impact on TMT1 instability has not been fully explored. This study aimed to investigate the TMT1 morphology and its potential correlation with HV and TMT1 instability. METHODS: Weightbearing computed tomography (WBCT) scans of 82 consecutive feet with HV and 79 controls were reviewed in this case-control study. Three-dimensional (3D) models of TMT1 were constructed using Mimics software and WBCT scans. The height of the TMT1 facet (FH) and the superior, middle, and inferior facet width (SFW, MFW, and IFW) were measured on anteroposterior view of the first metatarsal base. On the lateral view, the inferior lateral facet height and angle (ILFH and ILFA) were measured. TMT1 instability was evaluated using the TMT1 angle. RESULTS: Compared with the control group, the HV group had a significantly wider MFW (9.9 mm in HV, 8.7 mm in control), lower ILFH (1.7 mm in HV, 2.5 mm in control), smaller ILFA (16.3 degrees in HV, 24.5 degrees in control), and larger TMT1 angle (1.9 degrees in HV, 0.9 degrees in control) (all P < .05). No significant differences were found between the 2 groups in FH, SFW, and IFW (all P > .05). The study identified 4 types of TMT1 morphology: continuous-flat, separated-flat, continuous-protruded, and separated-protruded. The continuous-flat type possessed significantly larger HVA, IMA, and TMT1 angles compared with other types (all P < .001). CONCLUSION: This study indicates a potential association between TMT1 morphology and the severity of HV and identifies 4 TMT1 types. Notably, the continuous-flat type is found to be associated with more severe HV and TMT1 instability. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Collagen for neural tissue engineering: Materials, strategies, and challenges.

Neural tissue engineering (NTE) has made remarkable strides in recent years and holds great promise for treating several devastating neurological disorders. Selecting optimal scaffolding material is crucial for NET design strategies that enable neural and non-neural cell differentiation and axonal growth. Collagen is extensively employed in NTE applications due to the inherent resistance of the nervous system against regeneration, functionalized with neurotrophic factors, antagonists of neural growth inhibitors, and other neural growth-promoting agents. Recent advancements in integrating collagen with manufacturing strategies, such as scaffolding, electrospinning, and 3D bioprinting, provide localized trophic support, guide cell alignment, and protect neural cells from immune activity. This review categorises and analyses collagen-based processing techniques investigated for neural-specific applications, highlighting their strengths and weaknesses in repair, regeneration, and recovery. We also evaluate the potential prospects and challenges of using collagen-based biomaterials in NTE. Overall, this review offers a comprehensive and systematic framework for the rational evaluation and applications of collagen in NTE.

Cartilage Lacuna-Inspired Microcarriers Drive Hyaline Neocartilage Regeneration.

Cartilage equivalents from hydrogels containing chondrocytes exhibit excellent potential in hyaline cartilage regeneration, yet current approaches have limited success at reconstituting the architecture to culture nondifferentiated chondrocytes in vitro. In this study, specially designed lacunar hyaluronic acid microcarriers (LHAMCs) with mechanotransductive conditions that rapidly form stable hyaluronic acid (HA) N-hydroxy succinimide ester (NHS-ester) are reported. Specifically, carboxyl-functionalized HA is linked to collagen type I via amide-crosslinking, and gas foaming produced by ammonium bicarbonate forms concave surface of the microcarriers. The temporal 3D culture of chondrocytes on LHAMCs uniquely remodels the extracellular matrix to induce hyaline cartilaginous microtissue regeneration and prevents an anaerobic-to-aerobic metabolism transition in response to the geometric constraints. Furthermore, by inhibiting the canonical Wnt pathway, LHAMCs prevent ß-catenin translocation to the nucleus, repressing chondrocyte dedifferentiation. Additionally, the subcutaneous implantation model indicates that LHAMCs display favorable cytocompatibility and drive robust hyaline chondrocyte-derived neocartilage formation. These findings reveal a novel strategy for regulating chondrocyte dedifferentiation. The current study paves the way for a better understanding of geometrical insight clues into mechanotransduction interaction in regulating cell fate, opening new avenues for advancing tissue engineering.

Safety and efficacy of intra-articular injection of platelet-rich plasma for the treatment of ankle osteoarthritis: a systematic review and meta-analysis.

PURPOSE: To evaluate the safety and efficacy of platelet-rich plasma (PRP) intra-articular injective treatments for ankle osteoarthritis (OA). METHODS: A systematic literature search was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in PubMed, Scopus, Embase, Google Scholar, and the Cochrane library until May 2022. Both randomized and non-randomized studies were included with the assessment of the risk of bias. We recorded the participant's age, gender, type of PRP, injection volume, the kit used, and activating agent. We subsequently assessed the short-term and long-term efficacy of PRP using the functional scores and visual analog scale (VAS). RESULTS: We included four studies with a total of 127 patients, with a mean age of 56.1 years. 47.2% were male (60/127), according to eligibility criteria. There were three cohort studies and one randomized controlled trial (RCT) study, and no study reported severe adverse events. All included studies used the Leukocyte-poor PRP. Short-term follow-up results suggested significant improvement of the American Orthopaedic Foot and Ankle Society (AOFAS) score in the PRP injection group compared to the control group (n = 87 patients; MD: 6.94 [95% CI: 3.59, 10.29]; P < 0.01). Consistently, there was a statistical difference in AOFAS score between PRP injection and control groups in the final follow-up (≥ 6 months) (n = 87 patients; MD: 9.63 [95% CI: 6.31, 12.94]; P < 0.01). Furthermore, we found a significant reduction in VAS scores in the PRP groups at both the short-term follow-up (n = 59 patients; MD, - 1.90 [95% CI, - 2.54, - 1.26]; P < 0.01) and the ≥ six months follow-up (n = 79 patients; MD, - 3.07 [95% CI, - 5.08, - 1.05]; P < 0.01). The improvement of AOFAS and VAS scores at ≥ six months follow-up reached the minimal clinically important difference (MCID). Nevertheless, the treatment effect of AOFAS and VAS scores offered by PRP at short-term follow-up did not exceed the MCID. Substantial heterogeneity was reported at the ≥ six months follow-up in VAS scores (I2: 93%, P < 0.01). CONCLUSION: This meta-analysis supports the safety of PRP intra-articular injection for ankle OA. The improvements of AOFAS and VAS scores in the PRP group at short-term follow-up do not exceed the MCID to be clinically significant. PRP injection provides significant improvement of AOFAS score and reduced pain at ≥ six months follow-up. The efficacy of PRP should be interpreted with caution regarding the high heterogeneity and the scarcity of available literature, which urges large-scale RCTs with longer follow-up to confirm the potential efficacy of PRP injection for ankle OA.

Arthroscopically assisted versus open reduction internal fixation for ankle fractures: a systematic review and meta-analysis.

BACKGROUND: Open reduction and internal fixation were routinely used to treat patients with unstable ankle fractures (ORIF). However, some patients may experience persistent ankle pain and disability following ORIF due to untreated intra-articular lesions. Moreover, ankle fractures may be treated with arthroscopically assisted reduction and internal fixation (ARIF). This study aimed to compare the feasibility and benefits of ARIF versus ORIF for ankle fractures. METHODS: We performed this meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A systematic search was conducted for comparative studies comparing ARIF and ORIF for ankle fractures. Nine studies were included in the analysis of clinical and secondary outcomes. In summary, we calculated the mean difference (MD), risk ratio (RR), confidence interval, and p value. RESULTS: This meta-analysis demonstrated that the ARIF group achieved a higher Olerud-Molander Ankle (OMA) score (MD: 6.6; 95% CI 0.20 to 13.0; p = 0.04) and lower visual analog scale (VAS) score (MD: - 0.36; 95% CI - 0.64 to - 0.10; p = 0.01) at the final follow-up. Nevertheless, the smallest treatment effect of OMA score and VAS score did not exceed the minimum clinically important difference (MCID). There were longer surgery time (MD: 15.0; 95% CI 10.7 to 19.3; p < 0.01) and lower complication rates (RR: 0.53; 95% CI 0.31 to 0.89; p = 0.02) in ARIF compared with ORIF. The random-effect model suggested no significant difference in the arthritis change rate between the two groups. CONCLUSION: In summary, the results of this meta-analysis indicated that ARIF and ORIF are comparable in terms of providing pain relief and improving function for patients with ankle fractures. Therefore, the choice between the two techniques should be based on the patient's individual factors and the surgeon's personal preference.

Bioink derived from human placenta supporting angiogenesis.

Bioprinting is an emerging approach for constructing sophisticated tissue analogues with detailed architectures such as vascular networks, which requires bioink to fulfill the highly printable property and provide a cell-friendly microenvironment mimicking a native extracellular matrix (ECM). Here, we developed a human placental ECM-derived bioink (hp-bioink) meeting the requirements of 3D printing for printability and bioactivity. We first decellularized the human placenta, followed by enzymatic digestion, dialysis, lyophilization, and re-solubilization to convert the extracts into hp-bioink. Then, we demonstrated that 3%-5% of hp-bioink can be printed with self-standing and 1%-2% of hp-bioink can be embedded and printed within suspended hydrogels. Moreover, hp-bioink supports human umbilical vein endothelial cell assemblyin vitroand angiogenesis in micein vivo. Our research enriches the bank of human-derived bioinks, and provides a new opportunity to further accelerate bioprinting research and application.

Platinum clusters anchored on sulfur-doped ordered mesoporous carbon for chemoselective hydrogenation of halogenated nitroarenes.

Chemoselective hydrogenation of unsaturated organic compounds is a significant research topic in the catalysis field. Herein, a sulfur-doped ordered mesoporous carbon (SMC) material was prepared to anchor ultrafine platinum (Pt) clusters for the chemoselective hydrogenation of halogenated nitroarenes. The confinement effect of the ordered pores and the strong metal-support interaction caused by Pt clusters and sulfur atoms, efficiently suppress the aggregation and regulate the electronic states of the ultrafine Pt clusters. Thus, the hydrogenation of parachloronitrobenzene (p-CNB) shows high selectivity catalyzed by the ultrafine Pt clusters with electron-rich states. Meanwhile, the catalytic performance of the hydrogenation reaction catalyzed by Pt/SMC is capable of being maintained after at least 5 cycles, and the catalytic universality can also be applied to different halogenated nitroarenes hydrogenation. Therefore, this study may promote the research into the construction of noble metal-based catalysts for chemoselective hydrogenation reactions in green and sustainable chemical processes.

Microcarriers in application for cartilage tissue engineering: Recent progress and challenges.

Successful regeneration of cartilage tissue at a clinical scale has been a tremendous challenge in the past decades. Microcarriers (MCs), usually used for cell and drug delivery, have been studied broadly across a wide range of medical fields, especially the cartilage tissue engineering (TE). Notably, microcarrier systems provide an attractive method for regulating cell phenotype and microtissue maturations, they also serve as powerful injectable carriers and are combined with new technologies for cartilage regeneration. In this review, we introduced the typical methods to fabricate various types of microcarriers and discussed the appropriate materials for microcarriers. Furthermore, we highlighted recent progress of applications and general design principle for microcarriers. Finally, we summarized the current challenges and promising prospects of microcarrier-based systems for medical applications. Overall, this review provides comprehensive and systematic guidelines for the rational design and applications of microcarriers in cartilage TE.

Minimally Invasive vs. Open Surgery for Hallux Valgus: A Meta-Analysis.

Purpose: In recent years, minimally invasive surgery (MIS) for hallux valgus has emerged and gained popularity. To date, evidence on the benefits of MIS for hallux valgus is still controversial. This updated meta-analysis aimed to comprehensively evaluate the efficiency of MIS vs. open surgery for hallux valgus. Methods: A systematic literature search of PubMed, Embase, and the Cochrane Library was performed. Two independent reviewers conducted data extraction and analyzed data with R software. Data were presented with risk ratio (RR) and standardized mean difference (SMD) along with 95% confidence interval (CI). Results: A total of 22 studies in which there were 790 ft treated with the MIS procedure and 838 ft treated with an open procedure were included. The correction of sesamoid position was better in the MIS group. The post-operative distal metatarsal articular angle (DMAA) of the MIS group was lower. There was less pain at the early phase in the MIS group. The MIS group had a shorter surgery time and shorter hospitalization time compared with the open group. Our meta-analysis revealed no statistically significant difference in hallux valgus angle (HVA), first intermetatarsal angle (IMA), the first metatarsal shortening, the American Orthopedic Foot and Ankle Society (AOFAS) score, visual analog scale (VAS) score at the final follow-up or complication rate (when all studies were considered). When taking into consideration only randomized controlled trial (RCT), the AOFAS score was higher in the MIS group while HVA, IMA, DMAA, and complication rate remained no significance. Post-operative IMA of the MIS group was significantly lower when only studies reporting the second-generation (2G) MIS were included. When just studies adopting the third-generation (3G) MIS were included, the HVA and DMAA were lower in the MIS group. Conclusion: The MIS procedures were more effective than open surgeries in the treatment of hallux valgus. Moreover, the MIS group achieved better radiologic and clinical outcomes compared with the open group.

Excessive mechanical strain accelerates intervertebral disc degeneration by disrupting intrinsic circadian rhythm.

Night shift workers with disordered rhythmic mechanical loading are more prone to intervertebral disc degeneration (IDD). Our results showed that circadian rhythm (CR) was dampened in degenerated and aged NP cells. Long-term environmental CR disruption promoted IDD in rats. Excessive mechanical strain disrupted the CR and inhibited the expression of core clock proteins. The inhibitory effect of mechanical loading on the expression of extracellular matrix genes could be reversed by BMAL1 overexpression in NP cells. The Rho/ROCK pathway was demonstrated to mediate the effect of mechanical stimulation on CR. Prolonged mechanical loading for 12 months affected intrinsic CR genes and induced IDD in a model of upright posture in a normal environment. Unexpectedly, mechanical loading further accelerated the IDD in an Light-Dark (LD) cycle-disrupted environment. These results indicated that intrinsic CR disruption might be a mechanism involved in overloading-induced IDD and a potential drug target for night shift workers.

Modified pedicle screw-rod versus anterior subcutaneous internal pelvic fixation for unstable anterior pelvic ring fracture: a retrospective study and finite element analysis.

OBJECTIVES: This study compared the stability and clinical outcomes of modified pedicle screw-rod fixation (MPSRF) and anterior subcutaneous internal pelvic fixation (INFIX) for the treatment of anterior pelvic ring fractures using the Tornetta and Matta grading system and finite element analyses (FEA). METHODS: In a retrospective review of a consecutive patient series, 63 patients with Orthopaedic Trauma Association (OTA)/Arbeitsgemeinschaft für Osteosynthesefragen (AO) type B or C pelvic ring fractures were treated by MPRSF (n = 30) or INFIX (n = 33). The main outcome measures were the Majeed score, incidence of complications, and adverse outcomes, and fixation stability as evaluated by finite element analysis. RESULTS: Sixty-three patients were included in the study, with an average age of 34.4 and 36.2 in modified group and conventional group, respectively. Two groups did not differ in terms of the injury severity score, OTA classification, cause of injury, and time to pelvic surgery. However, the MPSRF group had a rate of higher satisfactory results according to the Tornetta and Matta grading system than the conventional group (73.33% vs 63.63%) as well as a higher Majeed score (81.5 ± 10.4 vs 76.3 ± 11.2), and these differences were statistically significant at 6 months post-surgery. FEA showed that MPSRF was stiffer and more stable than INFIX and had a lower risk of implant failure. CONCLUSIONS: Both MPSRF and INFIX provide acceptable biomechanical stability for the treatment of unstable anterior pelvic ring fractures. However, MPSRF provides better fixation stability and a lower risk of implant failure, and can thus lead to better clinical outcomes. Therefore, MPSRF should be more widely applied to anterior pelvic ring fractures.

Decorin inhibits nucleus pulposus apoptosis by matrix-induced autophagy via the mTOR pathway.

Decorin (Dcn) is a member of the class I small leucine-rich proteoglycans, whose expression in the nucleus pulposus (NP) of intervertebral discs (IVDs) has been shown to increase with aging in humans and sheep. Dcn induces autophagy in endothelial cells; however, its precise role in NP and IVD degeneration during aging is not well understood. We addressed this question in the present study by treating rat nucleus pulposus cells (NPCs) with different concentrations of Dcn. The Western blot analysis and terminal deoxynucleotidyl transferase dUTP nick end labeling assay results showed that Dcn treatment induced autophagy and decreased apoptosis caused by interleukin (IL)-1ß application. This effect was dependent on the protein kinase B/mechanistic target of rapamycin (mTOR)/p70 S6 kinase signaling. Dcn treatment also decreased the expression of matrix metalloproteinase-3 and -13 and decreased the IL-1ß-induced attenuation of collagen type II and aggrecan levels. The role of Dcn in stimulating autophagy was further supported by the fact that the observed effects were abrogated by knocking down autophagy-related protein 7 with Atg7 small interfering RNA. Thus, Dcn protects NPCs in IVDs from IL-1ß-induced apoptosis and degeneration by promoting autophagy through mTOR signaling.

Modified internal fixator for anterior pelvic ring fractures versus conventional two-screw fixation.

PURPOSE: The present study aims to evaluate the short-term clinical effects and complications of modified three-screw fixation and conventional two-screw fixation for treating anterior pelvic ring fractures. METHODS: A retrospective study of 51 patients with type B fractures was performed. 25 patients (modified group) were treated with modified three-screw fixation and the other 26 patients (conventional group) with conventional two-screw fixation. Outcome measures included operation time, intraoperative blood loss, hospital stays, postoperative complications and the Majeed score at postoperatively 2 months, 3 months, 1 year and the time of implant removal. RESULTS: The mean operative times and mean blood loss for modified three-screw fixation versus conventional two-screw fixation bilateral were 54.8 ± 10.7 min versus 32.3 ± 9.9 min, and 153.3 mL versus 550.0 mL (p < 0.001), respectively. However, the Majeed score was better in modified group at postoperatively 2 months (75.6 ± 9.5 vs. 69.7 ± 8.3, p = 0.008) and 3 months (80.3 ± 10.7 vs. 75.1 ± 11.9, p = 0.014). There was no statistical difference between two groups at the time of implant removal (82.1 ± 9.3 vs. 80.9 ± 8.8, p = 0.272) and postoperatively 1 year (83.5 ± 7.8 vs 82.6 ± 8.2, p = 0.723). No patients experienced surgical wound infection, deep vein thrombosis, delayed union or nonunion, implant loosening or rupture. One patient complained of tardive unilateral thigh pain at postoperatively 4 months in conventional group. CONCLUSIONS: Both modified three-screw fixation and conventional two-screw fixation could ultimately afford satisfactory clinical and radiological outcomes with less complication for anterior pelvic ring fractures. The modified three-screw fixation might have better biomechanical strength and faster pelvic rehabilitation.

Solvent-free synthesis of symmetric methylene diesters via direct reaction of aromatic carboxylates with 1,n-dihaloalkanes.

An efficient methodology for the synthesis of symmetrical methylene diesters was developed through direct reaction of various aromatic carboxylates with 1,n-dihaloalkanes under solvent-free conditions. This strategy offers a high product yield, facile work-up and purification, and an environmentally friendly approach to obtain long-chain methylene carboxylate scaffolds with increased diversity.

Inhibition of Y1 Receptor Promotes Osteogenesis in Bone Marrow Stromal Cells via cAMP/PKA/CREB Pathway.

Inhibition of neuropeptide Y1 receptor stimulates osteogenesis in vitro and in vivo. However, the underlying mechanisms involved in these effects remain poorly understood. Here we identify the effects of Y1 receptor deficiency on osteogenic differentiation in human bone marrow stromal cells (BMSCs) by using genetic and pharmacological regulation, and to explore the pathways mediating these effects. In BMSCs, inhibition of Y1 receptor stimulates osteogenesis and upregulates the expression levels of the master transcriptional factor RUNX2. Mechanistically, Y1 receptor deficiency increases the levels of intracellular cAMP, which via protein kinase A (PKA) mediated pathways results in activation of phospho-CREB (p-CREB). We find RUNX2 activation induced by Y1 receptor deficiency is reversed by H-89, a PKA inhibitor. These results indicate Y1 receptor deficiency activates PKA-mediated phosphorylation of CREB, leading to activation of RUNX2 and enhances osteogenic differentiation in BMSCs. In conclusion, these data indicate that Y1 receptor deficiency promotes osteogenic differentiation by RUNX2 stimulation through cAMP/PKA/CREB pathway.

Multifunctional Smart Yolk-Shell Nanostructure with Mesoporous MnO2 Shell for Enhanced Cancer Therapy.

Manganese dioxide (MnO2) nanostructures have aroused great interest among analytical and biological medicine researchers as a unique type of tumor microenvironment (TME)-responsive nanomaterial. However, reliable approaches for synthesizing yolk-shell nanostructures (YSNs) with mesoporous MnO2 shell still remain exciting challenges. Herein, a YSN (size, ∼75 nm) containing a mesoporous MnO2 shell and Er3+-doped upconversion/downconversion nanoparticle (UCNP) core with a large cavity is demonstrated for the first time. This nanostructure not only integrates diverse functional components including MnO2, UCNPs, and YSNs into one system but also endows a size-controllable hollow cavity and thickness-tunable MnO2 layers, which can load various guest molecules like photosensitizers, methylene blue (MB), and the anticancer drugs doxorubicin (DOX). NIR-II fluorescence and photoacoustic (PA) imaging from UCNP and MB, respectively, can monitor the enrichment of the nanomaterials in the tumors for guiding chemo-photodynamic therapy (PDT) in vivo. In the TME, degradation of the mMnO2 shell by H2O2 and GSH not only generates Mn2+ for tumor-specific T1-MR imaging but also releases O2 and drugs for tumor-specific treatment. The result confirmed that imaging-guided enhanced chemo-PDT combination therapy that benefited from the unique structural features of YSNs could substantially improve the therapeutic effectiveness toward malignant tumors compared to monotherapy.