Delivery System Research Articles

A Journey Along the Boulevard of Bioactive Compounds from Natural Sources, with Cosmetic and Pharmaceutical Potential: Bee Venom, Cobra Venom, Ficus carica

Animal venom and plant extracts have been used since ancient times in traditional medicine worldwide. Natural components, valued for their safety and effectiveness, have been consistently used in cosmetic and pharmaceutical applications. We propose a journey along the boulevard of active compounds from natural sources, where bee venom (BV), cobra venom (CV), and Ficus carica reveal their individual therapeutic and cosmetic properties. The originality of this review lies in exploring the synergy of these bioactive sources, an approach that has not been presented in the literature. Although BV, CV, and Ficus carica have different origins and compositions, they have multiple common pharmacological and cosmetic actions, which make them ideal for inclusion in various products that can be used for skin care and health in general. Their anti-inflammatory, antioxidant, immunomodulatory, antimicrobial, neuroprotective, and regenerative properties give them an essential role in the creation of potential innovative and effective products in the pharmaceutical and cosmetics industry. Although many plant extracts have antioxidant and anti-inflammatory properties, Ficus carica was chosen due to its complex biochemical composition, which provides valuable benefits in skin regeneration and protection against oxidative stress. According to the International Nomenclature of Cosmetic Ingredients (INCI), Ficus carica is used in the form of an extract of fruits, leaves, juice, bark or stem, each having specific applicability in topical formulations; due to the diversity of bioactive compounds, it can amplify the effectiveness of BV and CV, helping to enhance their beneficial effects and reducing the risk of adverse effects, due to its well-tolerated nature. Thus, this combination of natural ingredients opens up new perspectives in the development of innovative products, optimizing efficiency and maintaining a favorable safety profile. In this context, due to the reported experimental results, the three natural sources caught our attention, and we conceived the present work, which is a review made following the analysis of the current progress in the study of the bioactive compounds present in BV, CV, and Ficus carica. We focused on the novelties regarding pharmacological and cosmetic actions presented in the literature, and we highlighted the safety profile, as well as the modern approaches regarding the delivery and transport systems of the active substances from the three natural sources, and we evaluated their prospects in therapeutic and cosmetic use. This paper not only expands our knowledge of bioactive compounds, but it can also generate new ideas and motivations for the research and development of innovative treatments and skincare methods.

Correction: Jin et al. A pH-Responsive DNA Tetrahedron/Methotrexate Drug Delivery System Used for Rheumatoid Arthritis Treatment. J. Funct. Biomater. 2023, 14, 541

In the original publication [...]

Development, characterization, and assessment of PLAROsomal vesicular system of curcumin for enhanced stability and therapeutic efficacy

Abstract Background Curcumin (CUR) is a natural polyphenol and one of the key phytoconstituents found in the rhizomes of Curcuma Longa. It exhibits various pharmacological properties, encompassing antioxidant, anticancer effects, antiseptic, and anti-inflammatory, among several others. A significant drawback of using CUR is its limited bioavailability, which primarily depends on gut microorganisms responsible for converting it into its bioavailable form. Therefore, the contemporary study intended to formulate a novel PLAROsomal vesicular delivery of CUR, i.e., CUR-PLAROsomes employing a design of experiments approach to examine the influence of various process parameters, such as particle size and drug percentage release. Result The prepared CUR-PLAROsomes were characterized for their physicochemical properties using various hyphenated tools. The CUR-PLAROsomes exhibited sizes ranging from 40 to 300 nm, and the optimized batch demonstrated a drug entrapment of 86.38 ± 0.22%. In-vitro anticancer studies were conducted using human colorectal adenocarcinoma cells (COLO320DM) and human breast adenocarcinoma (MCF-7). CUR-PLAROsomes exhibited significant in-vivo anti-inflammatory potential against carrageenan-induced paw edema. CUR-PLAROsomes were more potent against COLO320DM and MCF-7 cell lines, even at lower concentrations, than pure CUR. Conclusion Furthermore, based on the observations, it exhibits potential as an anti-inflammatory agent, suggesting that PLAROsomes are an effective vesicular drug delivery system. Highlights Newly introduced PLARosome is a next generation of Liposomes which have gain popularity owing to its better adaptability to overcome leakage problem of vesicular drug delivery system. This is the pioneer attempt to prepare Curcumin-loaded PLARosome as an anti-cancer and anti-inflammatory activity. Nano size of the PLAROsomes may contribute to enhance the efficacy of Curcumin as a target specific drug delivery system. Site specific delivery of phytoconstituents is possible by use of PLAROsomes as a novel drug delivery system. Graphical abstract

Physical, biochemical, and biological characterization of olive-derived lipid nanovesicles for drug delivery applications

AbstractExtracellular vesicles (EVs) have shown great promise as drug delivery system (DDS). However, their complex and costly production limit their development for clinical use. Interestingly, the plant kingdom can also produce EV-like nanovesicles that can easily be isolated and purified from a large quantity of raw material at a high yield. In this study, olive-derived nanovesicles (ODNVs) were isolated from raw fruits using serial centrifugations and their physical and biological features characterized to demonstrate their promising potential to be used as a DDS. Nanotracking particle analysis indicated an average size of 109.5 ± 3.0 nm and yield of 1012 ODNVs/mL for the purest fraction. Microscopy imaging, membrane fluidity assay and lipidomics analysis showed the presence of a rich lipid bilayer that significantly varied between different sources of ODNVs but showed a distinct signature compared to human EVs. Moreover, ODNVs were enriched in PEN1 and TET8 compared to raw fruits, suggesting an extracellular origin. Interestingly, ODNVs size and yield stayed unchanged after exposure to high temperature (70 °C for 1 h), wide pH range (5–10), and 50–100 nm extrusion, demonstrating high resistance to physical and chemical stresses. This high resistance allowed ODNVs to stay stable in water at 4 °C for a month, or with the addition of 25 mM trehalose for long-term freezing storage. Finally, ODNVs were internalized by both 2D and 3D cell culture without triggering significant cytotoxicity and immunogenicity. Importantly, the anticancer drug doxorubicin (dox) could be loaded by passive incubation within ODNVs and dox-loaded ODNVs decreased cell viability by 90% compared to only 70% for free dox at the same concentration, indicating a higher efficiency of drug delivery by ODNVs. In addition, this high cytotoxicity effect of dox-loaded ODNVs was shown to be stable after a 2-week storage at 4 °C. Together, these findings suggested that ODNVs represent a promising candidate as drug nanocarrier for various DDS clinical applications, as demonstrated by their biocompatibility, high resistance to stress, good stability in harsh environment, and improvement of anticancer drug efficacy.

Tripolar Bolalipids as Key Components of Sustained-Release Drug Delivery Systems

Tripolar Bolalipids as Key Components of Sustained-Release Drug Delivery Systems

Formulation development, characterization, and mechanistic PBPK modeling of metoclopramide loaded halloysite nanotube (HNT) based drug-in-adhesive type transdermal drug delivery system

Formulation development, characterization, and mechanistic PBPK modeling of metoclopramide loaded halloysite nanotube (HNT) based drug-in-adhesive type transdermal drug delivery system

Development of a Diabetes Navigator Toolkit to Support Diabetes Technology Uptake: The IMPACT Toolkit

Advanced diabetes technologies (ADTs), including continuous glucose monitoring devices, insulin pumps, and automated insulin delivery systems, improve glycemic control in type 1 diabetes but are underutilized, particularly in minority and underserved populations. This article reports on a qualitative study to develop a diabetes toolkit. Participants identified barriers to the use of ADTs and proposed solutions to these barriers, which were then incorporated into a diabetes toolkit designed for use by a diabetes navigator or other diabetes care team members seeking to improve the uptake and sustained use of ADTs.

Synthetic Biology-Enabled Engineering of Probiotics for Precision and Targeted Therapeutic Delivery Applications

Probiotics, defined as live microorganisms that offer health benefits when consumed in adequate amounts, have traditionally been used to maintain gastrointestinal (GI) health. They are effective in managing conditions such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and antibiotic-associated diarrhea. Recent research, however, has expanded their potential applications beyond the GI tract to include immune modulation, metabolic regulation, and mental health support. Despite these advances, conventional probiotics face limitations such as instability in harsh environments, lack of precise targeting, and ineffective control over drug release. This review explores the application of synthetic biology in addressing these limitations, emphasizing how tools such as CRISPR-Cas systems, synthetic gene circuits, and plasmid-based mechanisms enhance the stability, functionality, and specificity of engineered probiotics for therapeutic delivery. Applications of synthetic biology-enabled probiotics are examined across a range of health contexts, including GI health, cancer therapy, metabolic disorders, immune modulation, and mental well-being. Synthetic biology tools provide precise genetic modifications that improve the stability, viability, and functionality of engineered probiotics, enabling more targeted therapeutic delivery. Additionally, technologies such as encapsulation support probiotic survival, while gene circuits allow programmable, stimulus-responsive therapeutic release. As synthetic biology continues to advance, the development of programmable probiotics holds promise for personalized, targeted medicine, positioning probiotics as living therapeutics and patient-friendly alternatives to conventional therapeutic delivery systems.

The Strategies to Improve Primary Health Care Services: A Scoping Review

Context: Evaluation of health policies and identification of their challenges are vital for improving and implementing reforms in the healthcare system. The present study was conducted to identify interventions aimed at improving primary healthcare (PHC) services in Iran. Evidence Acquisition: This research utilizes a scoping review to examine reform interventions in PHC services across 10 selected countries: Qatar, Oman, Turkey, Georgia, Armenia, United Arab Emirates, Saudi Arabia, Bahrain, Kazakhstan, and Kuwait. The study covers areas such as the PHC delivery system, human resource management, financial mechanisms, and the framework of community participation and intersectoral collaboration from 2010 to 2022. Results: The main reform strategies for PHC systems in the reviewed countries included the establishment of family medical centers with nurse support as a comprehensive strategy for service provision in public health centers; providing comprehensive and quality healthcare service packages including maternal and child health, infectious disease immunization, chronic disease monitoring, and dental care services; health education; access to essential medications; improvement of electronic health services; implementation of health promotion and continuous prevention programs; capacity enhancement; and a greater focus on health screening programs and grading of healthcare centers. Conclusions: The major findings from the reviewed countries indicate that healthcare policymakers focus on providing preventive care services, reducing maternal and child mortality, and increasing life expectancy. Programs such as referral systems, service grading, and the adoption of electronic health services are part of their reform agenda.

Production of Polylactide Nanoparticles Loaded With Isoniazid and Vitamin C: A Promising Candidate for the Treatment of Resistant Forms of Tuberculosis

ABSTRACTNowadays, the method of directed transport of drugs is becoming increasingly important in medicine and pharmacology. It allows for increasing the concentration of delivered substances in a certain place and blocking or severely limiting their accumulation in healthy organs and tissues. One of the promising drug carriers used in the development of controlled drug delivery systems is polylactic acid (PLA). We were interested in using biodegradable polymeric nanoparticles (NPs) loaded with isoniazid (INH) and vitamin C (VC) which have sustained action, targeted delivery, high efficacy, and low toxicity. It will help to expand the use of these simple drugs for the rapid treatment of multidrug‐resistant forms of tuberculosis. Thus, in this work, PLA‐INH‐VC NPs were prepared by double emulsion method where several factors affecting particle size were investigated. TGA/DSC and IR spectroscopy studies identified the presence of molecularly dispersed drugs (INH and VC) in polylactide nanoparticles. VC was found to reduce the degradation of the polymer and thus prolonged the release of the drug from the polymer matrix. PLA‐INH‐VC nanoparticles were analyzed for mycobacterial activity and the nanoparticles were found to inhibit the growth of INH‐resistant mycobacteria.

Can nanotechnology and genomics innovations trigger agricultural revolution and sustainable development?

At the dawn of new millennium, policy makers and researchers focused on sustainable agricultural growth, aiming for food security and enhanced food quality. Several emerging scientific innovations hold the promise to meet the future challenges. Nanotechnology presents a promising avenue to tackle the diverse challenges in agriculture. By leveraging nanomaterials, including nano fertilizers, pesticides, and sensors, it provides targeted delivery methods, enhancing efficacy in both crop production and protection. This integration of nanotechnology with agriculture introduces innovations like disease diagnostics, improved nutrient uptake in plants, and advanced delivery systems for agrochemicals. These precision-based approaches not only optimize resource utilization but also reduce environmental impact, aligning well with sustainability objectives. Concurrently, genetic innovations, including genome editing and advanced breeding techniques, enable the development of crops with improved yield, resilience, and nutritional content. The emergence of precision gene-editing technologies, exemplified by CRISPR/Cas9, can transform the realm of genetic modification and enabled precise manipulation of plant genomes while avoiding the incorporation of external DNAs. Integration of nanotechnology and genetic innovations in agriculture presents a transformative approach. Leveraging nanoparticles for targeted genetic modifications, nanosensors for early plant health monitoring, and precision nanomaterials for controlled delivery of inputs offers a sustainable pathway towards enhanced crop productivity, resource efficiency, and food safety throughout the agricultural lifecycle. This comprehensive review outlines the pivotal role of nanotechnology in precision agriculture, emphasizing soil health improvement, stress resilience against biotic and abiotic factors, environmental sustainability, and genetic engineering.

A review on lipid and polymeric nano-based 17-β-estradiol delivery systems: advances and challenges

17β-estradiol (E2) is an endogenous steroid hormone pivotal for the development of female secondary sexual characteristics and the maintenance of the female reproductive system. Its roles extend beyond these physiological functions, as E2 is employed in hormone replacement therapy to alleviate symptoms associated with menopause. Furthermore, E2 exhibits therapeutic potential in the management of osteoporosis, breast cancer, and various neurological and cardiovascular conditions, partly due to its anti-inflammatory effects via modulation of the MAPK/NFκB signaling pathway. Notwithstanding, the hydrophobic nature of E2 significantly hinders the formulation of efficacious delivery systems for its clinical deployment. Recent advances have highlighted nano-based delivery systems for E2 as a promising solution to this solubility challenge. This review critically examines contemporary nano-delivery strategies for E2, particularly emphasizing lipid and polymeric nanoparticle-based systems. These nanostructures are designed to enhance stability, biocompatibility, controlled release, and targeted delivery of E2, yet the selectivity of E2 delivery for therapeutic purposes remains an ongoing challenge. The novelty of this review lies in its focus on the advances in nano-based E2 delivery systems over the past decade, a topic not extensively covered in prior literature. We present a comprehensive analysis of the encapsulation of E2 within polymeric and lipid nanoparticles, underscoring the untapped potential of these strategies. This review identifies a significant research gap, advocating for intensified experimental investigations that could pave the way for the translation of nano-based E2 therapies from bench to bedside.

Therapeutic Potential of Cannabinoids in Glaucoma – Hit or Myth? - A Review

Introduction: Glaucoma is a leading cause of irreversible blindness, characterized by elevated intraocular pressure (IOP) that damages the optic nerve. Current treatments mainly focus on reducing IOP, but some patients do not respond adequately to conventional therapies. Cannabinoids, particularly Δ9-tetrahydrocannabinol (Δ9-THC), have been investigated as potential adjunctive treatments for glaucoma. Studies have shown varying effects of cannabinoids on IOP regulation, though their precise mechanisms remain unclear. Aim of Study: This study aims to evaluate the therapeutic potential of cannabinoids in the treatment of glaucoma by examining their effects on IOP, their mechanisms of action, and the risks and benefits associated with their use. Material and methods: A comprehensive literature review of studies on the therapeutic potential of cannabinoids in glaucoma was conducted using the PubMed database. Results and Conclusions: Cannabinoids, especially Δ9-THC, have demonstrated the ability to reduce IOP in both healthy individuals and glaucoma patients. However, the effect is typically short-lived, lasting only 3-4 hours. The efficacy of cannabinoids in reducing IOP is influenced by the method of administration (oral, intravenous, inhalation) and the delivery system used for topical application. Despite some promising results, the use of cannabinoids as a mainstream glaucoma treatment is limited by factors such as the short duration of action, the potential for addiction, and the occurrence of adverse effects like tachycardia, hypotension, and cognitive impairment. Although cannabinoids offer a unique approach to glaucoma management, further research is necessary to address these limitations and determine their long-term therapeutic viability.

Trials and tribulations of cell therapy for heart failure: an update on ongoing trials.

Heart failure (HF) remains a leading cause of mortality, responsible for 13% of all deaths worldwide. The prognosis for patients with HF is poor, with only a 50% survival rate within 5 years. A major challenge of ischaemia-driven HF is the loss of cardiomyocytes, compounded by the minimal regenerative capacity of the adult heart. To date, replacement of irreversibly damaged heart muscle can only be achieved by complete heart transplantation. In the past 20 years, cell therapy has emerged and evolved as a promising avenue for cardiac repair and regeneration. During this time, cell therapy for HF has encountered substantial barriers in both preclinical studies and clinical trials but the field continues to progress and evolve from lessons learned from such research. In this Review, we provide an overview of ongoing trials of cell-based and cell product-based therapies for the treatment of HF. Findings from these trials will facilitate the clinical translation of cardiac regenerative and reparative therapies not only by evaluating the safety and efficacy of specific cell-based therapeutics but also by establishing the feasibility of novel or underexplored treatment protocols such as repeated intravenous dosing, personalized patient selection based on pharmacogenomics, systemic versus intramural cell delivery, and epicardial engraftment of engineered tissue products.

Double-crosslinked hydrogels and hydrogel beads formed by garlic protein hydrolysates for bioactive encapsulation and gastrointestinal delivery.

Garlic protein is one of the main components of garlic. It has several beneficial characteristics. This study aimed to characterize a double crosslinked hydrogel formed with alginate, calcium ions (Ca2+), and garlic protein hydrolysates (GPH), and to develop hydrogel beads for targeted delivery of bioactive constituents to the gastrointestinal tract. The results indicated that the degree of GPH hydrolysis was approximately 3% following trypsin treatment. The inner structure of the double crosslinked hydrogel showed a honeycomb pattern, with solid-like gel rheology and improved texture properties at a 4% (w/v) GPH concentration. The GPH-based hydrogel beads demonstrated pH sensitivity, swelling in near-neutral and alkaline environments, and the encapsulated paclitaxel (PTX) exhibited an amorphous phase with preferential release in intestinal conditions. The GPH group also achieved greater drug encapsulation efficiency than a soy protein hydrolysate (SPH) group, and proteomic analysis suggested that lower molecular weight and peptide charge favored the formation of peptide-integrated double crosslinking hydrogels. This work indicated that GPH was helpful and could inspire the development of drug delivery systems involving GPH with the required mechanical strength and target-release properties. © 2024 Society of Chemical Industry.

Formulation, Development and Evaluation of Pulsatile Tablets of Etoricoxib

Aim: This research aimed to develop a pulsatile drug delivery system (PDDS) for etoricoxib, selective COX-2 inhibitor analgesic, to address the limitations of conventional formulations by releasing the drug at specific intervals aligned with the circadian rhythm of pain. Method: Core tablets containing Etoricoxib were prepared by direct compression with varied concentrations of croscarmellose sodium as a superdisintegrant. The optimized core tablets were coated using hydrophilic (HPMC K4M) and hydrophobic (ethyl cellulose) polymers in different ratios to create press-coated pulsatile tablets with varying lag times. Physical properties hardness, thickness, friability, and disintegration, drug content uniformity, and in vitro release were evaluated. Results: The core tablets exhibited rapid drug release, with batch C3 showing 98.61% release within 60 minutes. Press-coated formulations with different polymer ratios exhibited varying lag times, with batch F3 achieving the optimal balance—providing a 4-hour lag time and 96.6% drug release over 8 hours. Stability studies confirmed the physical and chemical stability of the optimized formulation (F3) over 6 months under accelerated conditions. Conclusion: The developed press-coated pulsatile tablets of etoricoxib successfully achieved a controlled lag time and sustained drug release profile, making them suitable for chronopharmacological management of pain. Keywords: Etoricoxib, Pulsatile Drug Delivery System, Chronopharmacology, Press-Coated Tablets. etc

Multiwavelength photobiomodulation in atrophic age-related macular degeneration.

To evaluate photobiomodulation (PBM) safety and efficacy in patient with atrophic AMD and to explore tissue effects using Spectrally Resolved Autofluorescence (SrAF) to identify a potential biomarker indicative of mitochondrial activity, the primary PBM target. This retrospective, non-comparative case series involved six eyes of five patients with atrophic AMD, conducted at the Medical Retina and Imaging Unit, IRCCS San Raffaele Hospital in Milan, Italy. At baseline and follow-ups (after one and three months) a complete ophthalmological assessment and multimodal imaging, including spectrally resolved autofluorescence (SrAF), were performed. PBM treatment (Valeda Light Delivery System - LumiThera) was administered in nine sessions over three weeks. The SrAF images were analyzed to evaluate the effect of the treatment. Six eyes of five patients with atrophic AMD received PBM at baseline. Best corrected visual acuity (BCVA), mean central macular thickness (CMT), mean retinal sensitivity on microperimetry and the atrophic area have remained stable. No eyes developed foveal atrophy after the treatment. The image analysis in SrAF showed an increase in the highlighted area of 4.89% after one month and 17.11% after three months. No adverse systemic or local side effects were reported. PBM is a safe treatment for the human retina. The evaluation of the retinal area within the green light spectrum (575 nm) in SrAF is a potential indirect biomarker of mitochondrial activity and could be used to assess treatment efficacy in clinical studies.

Timolol Maleate Microspheres: An Ingenious Carrier for Sustained Release Antihypertensive Formulation

Background: Timolol maleate is classified as a BCS Class I drug and functions as a non-selective β-adrenergic receptor blocker. Its ability to lower heart rate and cardiac output has led to its widespread use in the treatment of hypertension. Objective: Timolol maleate has a short half-life and is rapidly cleared from the body, which limits its therapeutic effectiveness, requiring frequent dosing and potentially affecting patient adherence. To overcome these challenges, sustained-release microspheres of Timolol maleate were developed using the ion gelation method. Method: The ion gelation technique was employed to create the microspheres due to its various advantages, including ease of use, scalability and gentle processing conditions. Results: All batches exhibited a comparatively lower swelling index in 0.1M HCl (pH 1.2) than in SIF (pH 6.8). It was observed that increasing the concentration of sodium alginate resulted in higher drug content. The microspheres were sized between 400 and 900 μm and demonstrated excellent flow characteristics. An optimized batch achieved an entrapment efficiency of 88.83% and released 92.15% of the drug over 7 hrs. Furthermore, stability studies conducted according to ICH Q1A(R2) for 3 months at 5±3°C and 25±2°C/60±5% RH indicated no significant changes in evaluation parameters. Conclusion: The optimized Timolol maleate-loaded microspheres effectively provided sustained drug release through the membrane over 7 hrs. This study contributes to the development of improved drug delivery systems for better hypertension management, addressing the unmet needs in patient compliance. Keywords: Timolol Maleate, Microspheres, Ion gelation method, Sodium alginate, Calcium chloride, Sustained release, Hypertension

Excitatory amino acids as therapeutic agents: Reversing neurodegenerative trajectory by tackling excitotoxicity.

Neurodegenerative diseases pose significant challenges to healthcare systems globally due to their complex etiology and relentless progression, often rendering conventional treatments ineffective. Recent advances have spotlighted excitatory amino acids, particularly D-amino acids, once considered as products of metabolism of the microbiota or deriving from food intake. This review explores the role of D-amino acids in mitigating excitotoxicity-a process characterized by excessive calcium influx through aberrant N-methyl-D-aspartate receptor (NMDAR) activation, which is implicated in the pathogenesis of diseases like Alzheimer's disease. By providing alternative pathways for neuronal signaling and protecting against excitotoxic damage, D-amino acids offer a novel approach to reversing neurodegenerative trajectories. Future research should focus on elucidating the detailed mechanisms of action of these compounds, evaluating their therapeutic potential through rigorous preclinical and clinical trials, and developing effective delivery systems to optimize their neuroprotective effects. This emerging field holds promise for developing innovative treatment strategies that could significantly improve outcomes for patients with neurodegenerative disorders.

FeS2@COF based nanocarrier for photothermal-enhanced chemodynamic/thermodynamic tumor therapy and immunotherapy via reprograming tumor-associated macrophages.

Developing high-performance nanomedicines to enhance antitumor efficacy remains a hot point in the field of biomedicine. In this study, we designed a versatile nanocomposite (FeS₂@COF-HA/AIPH) integrating covalent organic frameworks (COF) functionalized with pyrite (FeS₂) for synergistic photothermal (PTT), chemodynamic (CDT), thermodynamic (TDT) therapies, and immunotherapy. The superior photothermal effects and catalytic capabilities of FeS₂@COF enabled a minimally invasive PTT/CDT combination. The nanoplatform, with its mesoporous structure, also served as a drug delivery system, encapsulating the thermos-decomposable initiator AIPH. The hyaluronic acid (HA) coating not only improved tumor-targeting efficiency but also prevented nonspecific AIPH release. Under near-infrared (NIR) irradiation, the localized hyperthermia triggered AIPH decomposition, generating toxic alkyl radicals (•R) for TDT, further enhancing CDT efficiency. The combination of PTT, CDT, TDT, and immunotherapy led to potent antitumor effects with minimal systemic toxicity, both in vitro and in vivo. Notably, the nanoplatform effectively reprogrammed tumor-associated macrophages (TAMs) from an M2 to M1 phenotype, boosting antitumor immunity. This multifunctional platform thus offers a promising strategy for integrated PTT, CDT, TDT, and immune activation in tumor therapy.