Recent trends in liposomal drug efficiency of nanotechnology in photodynamic therapy for cancer

Abstract

Photodynamic therapy (PDT) has emerged as a clinically approved, non-invasive cancer treatment that induces tumor cell death through the intracellular generation of reactive oxygen species (ROS) upon exposure to non-ionizing radiation. Its effectiveness relies on the synergistic action of a photosensitizer (PS), light, and molecular oxygen, with the therapeutic response shaped by the PS’s selective accumulation in tumor-associated organelles such as mitochondria and lysosomes. Despite its clinical utility, conventional PDT faces significant challenges, including limited specificity, poor bioavailability. To address these limitations, recent advances in nanotechnology, particularly liposomal drug delivery systems, have demonstrated significant potential in enhancing the efficiency and selectivity of PDT. Liposomes, with their amphiphilic nature and biocompatibility, enable controlled PS release, enhanced tumor targeting, and reduced systemic toxicity. Furthermore, functionalization with ligands and integration of imaging agents have led to the development of multifunctional liposomal nanocarriers capable of simultaneous therapy and diagnosis (theranostics). This review discusses the evolving trends in liposome-based nanomedicine for PDT, including the incorporation of green nanotechnology approaches that utilize biologically derived agents to synthesize eco-friendly nanoparticles with improved photochemical performance. The review also emphasizes the role of surface modification strategies to boost cancer cell specificity, highlighting recent developments aimed at improving the clinical translation of liposome-based PDT systems for more precise and effective cancer treatment.

Graphical abstract

Keywords

Cancer / Nanotechnology / Nanoparticles / Photodynamic therapy / Reactive oxygen species

1 Introduction

Cancer is a general term encompassing a group of diseases characterized by the loss of normal cellular control mechanisms, leading to uncontrolled cell growth [1]. In simpler terms, cancer is a medical condition in which tumor cells proliferate uncontrollably [2,3]. Notably, cancer can develop in any part of the body. Among women, breast cancer is one of the most prevalent types, whereas prostate cancer is the most common in men. In both sexes, colorectal and lung cancers are among the most frequently diagnosed [4]. If left untreated or poorly managed, cancer can lead to severe, life-threatening complications and, ultimately, death [5,6]. Crucially, cancer often arises from a series of genetic alterations, a process commonly referred to as mutation [2,7]. Several risk factors contribute to cancer development, including aging, excessive alcohol consumption, obesity, viral infections, hormonal imbalances, tobacco smoking, and prolonged exposure to carcinogenic agents such as specific chemicals and radiation [8].

Currently, there are at least five primary conventional cancer treatment therapies: surgery, radiation therapy, chemotherapy, hormone therapy, and immunotherapy [9]. Depending on the type and stage of cancer, these treatments may be administered individually or in combination with one or more modalities, such as using ionizing radiation after surgery [10,11]. While conventional therapies offer significant benefits in cancer treatment, they also have the potential to cause severe long-term side effects, including central and peripheral neurotoxicity [12]. In addition, the development of treatment-resistant cancer cell populations, ineffectiveness against cancer stem cells, and the discontinuation of treatment due to increased toxicity can lead to significant challenges in cancer therapy [13,14]. This highlights the need for alternative, eco-friendly therapeutic approaches, with green-synthesized nanoparticles (NPs) and photodynamic therapy (PDT) emerging as promising candidates. However, after years of research on PDT, scientists have identified several limitations in the process, including imprecise drug targeting, low concentration of reactive oxygen species (ROS) generation, and low oxygen levels within the tumor microenvironment (TME) [15,16]. To address these challenges, leveraging the unique characteristics of the TME presents a promising strategy for developing sensitive nano-drug systems designed to enhance the therapeutic efficacy of anti-cancer treatments.

Liposomes were first described by British hematologist Alec D. Bangham in the early 1960s during his studies on phospholipid membranes. Their potential as drug delivery vehicles was recognized in the 1970s, and by the 1990s, liposomal formulations began reaching clinical use [17,18]. The first FDA-approved liposomal drug was Doxil®, a PEGylated liposomal formulation of doxorubicin for cancer treatment [19−21]. Since then, liposomes have been successfully used in treating cancer, fungal infections, and viral diseases, and are now being explored in vaccinology, gene therapy, and immunotherapy.

Structurally, liposomes are spherical vesicles composed of one or more phospholipid bilayers surrounding an aqueous core [22,23]. Due to their biocompatibility, structural versatility, and ability to encapsulate both hydrophilic and hydrophobic agents, liposomes have become one of the most widely used nanocarriers in biomedical applications, particularly for drug and gene delivery [24,25]. In addition, liposomes are primarily made from phospholipids, which are amphiphilic molecules containing a hydrophilic head and hydrophobic tail [26,27]. When dispersed in an aqueous medium, these phospholipids spontaneously arrange into bilayer structures [28]. The aqueous core of liposomes can encapsulate hydrophilic drugs, while hydrophobic drugs can be embedded within the lipid bilayer [22].

This review article highlights and provides a concise yet in-depth of PDT, outlining its tumoricidal process and the use of nanomaterials including lipid-based nanoparticles (NPs) such as liposomal silver NPs (AgNPs-Lip), liposomal gold NPs (AuNPs-Lip), and nanoscale metal-organic frameworks as photosensitizers (PSs). In addition, this review is different from earlier ones that mostly focused on metallic NPs in general. Herein, this review focuses on the use of liposomes as nanocarriers and how they can improve cancer theranostics, especially when it comes to drug-loading efficiency and targeted therapy. We further introduce a unique thematic focus on PSs, sub-cellular co-localization in cancer cells, and yet underexplored determinant of ROS production and later discuss ROS generation influences the therapeutic efficacy of PDT. Lastly, our comprehensive review fills critical gaps in literature but also highlights future perspectives with focus on guiding nanomaterial-based innovations for the treatment of resistant cancer.

2 Photodynamic therapy

Photodynamic therapy (PDT) is a clinically approved, non-invasive treatment that utilizes non-ionizing radiation to trigger tumor cell death through the intracellular production of ROS [29]. This type of cancer therapy is characterized by its reliance on both tumor cell selectivity and the preferential accumulation of a PS within specific cellular organelles, including the mitochondria, lysosomes, and endoplasmic reticulum [30]. It is important to note that, although intracellular ROS generation is a well-established mechanism of cytotoxicity during PDT, ROS can also be generated within the extracellular space, especially in systems that are based on NPs, where a sizable fraction of particles remain in the extracellular space. Furthermore, extracellular generation of ROS can cause damage to the extracellular matrix components and altering stromal and immunological interactions, which can ultimately aid in the remodeling of the tumor TME [31,32]. The effectiveness of PDT in cancer treatment is fundamentally governed by the interaction of three key components including light with a specific wavelength, a PS, and intercellular molecular oxygen (O₂) [33]. However, conventional PDT faces therapeutic challenges, such as limited specificity, as well as constraints related to light dose, wavelength (λ), and fluence rates [33,34]. To overcome the aforementioned limitations, recent research has shifted from the direct use of conventional PSs in PDT to the development of novel photochemical compounds integrated with nanomaterials, such as liposomes, to enhance drug delivery through nanotechnology [35,36]. While nanotechnology is a well-established field with applications in computing, environmental science, and medicine, green nanotechnology has emerged as an innovative therapeutic strategy. This approach utilizes oxidizing agents such as silver nitrate (AgNO₃) salts, tetrachloroauric acid (HAuCl₄), plant extracts, or plant-derived bioactive compounds to synthesize therapeutic green NPs with improved efficacy in PDT. Additionally, functionalization of these NPs with targeting moieties, such as anti-histamines, enhances their selectivity toward cancer cells, improving therapeutic precision. This review explores the most commonly employed nanoparticle-based drug delivery strategies in cancer therapy and further examines the photophysical and photochemical mechanisms underlying green nano-formulations in PDT.

2.1 Photophysical and photochemical processes in PDT: Basic knowledge

The basic mechanism of PDT involves the interactions of a three-component system consisting of a PS, specific λ of light, and O₂ to induce tumor cell death [37]. Unlike chemotherapy drugs, PSs used in PDT do not exert toxic effects on biological systems prior laser irradiation [38]. As depicted in the modified Jablonski energy diagram (Fig. 1), the illustration outlines a sequential series of photophysical and photochemical processes that occur following light absorption by a PS that is preferentially localized within tumor cells. These events ultimately result in the intracellular production of cytotoxic ROS. PSs excitation occurs when an intracellularly localized PS absorbs photon energy and interacts with biomolecules that have electromagnetic energy transitions matching those of the photon. This interaction promotes the PS from its ground singlet state (S₀) to an excited electronic state known as the singlet state (S₁). Once in the S₁ state, the PS can follow one of two possible pathways. The first involves a transition back to the S₀ state, releasing energy in the form of fluorescence. This photophysical process is primarily utilized in photodynamic diagnosis. The second possible pathway for the transition from the S₁ state to the S₀ state involves rearrangements of valence electrons through spin changes, accompanied by intersystem crossing (ISC), formation of the triplet state (T₁), internal conversion (IC), and phosphorescence. Notably, the T₁ state has a longer half-life compared to the S₁ state of an excited PS. In the presence of biomolecules or triplet-state molecules like ³O₂, the excited T₁ state of the PS can initiate photochemical reactions, which form the fundamental basis of PDT [39].

Beyond these photophysical processes, two primary photochemical pathways—Type I and Type II—are responsible for generating free radicals and ROS following PDT activation (Fig. 1). The Type I pathway operates through redox reactions, where the excited T₁ state of the PS transfers electrons or hydrogen ions to nearby biomolecules [40,41]. This interaction leads to the formation of superoxide anions (O₂^•–), hydroxyl radicals (OH^•), and hydrogen peroxide (H₂O₂) [40,42,43]. In contrast, the Type II pathway involves the direct transfer of energy from the excited T₁ state PS to ³O₂ in its ground triplet state, resulting in the production of cytotoxic singlet oxygen (¹O₂) [38,42]. The effectiveness of these photochemical reactions in PDT is influenced by factors such as the PS concentration, the availability of ³O₂, and the presence of suitable substrates. It is worth noting that these two pathways can occur concurrently in a competitive manner [44].

Analyzing ¹O₂ quantum yield (ΦΔ) plays a significant role in the assessment and optimization of photophysical and chemical properties of PSs for PDT and photoinduced biological applications [45,46]. The ability of a PS to generate reactive ¹O₂, the main cytotoxic agent that kills bacteria, viruses, or cancer cells during PDT, is directly reflected in ΦΔ. A substantial therapeutic impact is typically correlated with a high ¹O₂ ΦΔ [47,48]. Furthermore, comprehending ¹O₂ ΦΔ helps researchers and physicians in optimizing treatment duration, PS concentration, and light dose. In addition, ¹O₂ ΦΔ of any PS can be determined using either chemical trapping (indirect method) or direct detection method (using laser or monochromatic light (often a pulsed source)) [45]. Table 1 summarizes various classes of PSs along with their ¹O₂ ΦΔ.

2.2 Nanomaterials as carriers for photosensitizers

PDT has gained recognition as a promising cancer treatment strategy, utilizing PSs to produce ROS when exposed to light. Conventional organic PSs, including porphyrins, phthalocyanines, and chlorins, have been extensively employed in PDT [52,53]. However, advancements in nanotechnology have facilitated the development of nanomaterial-based PSs, providing greater stability, precise targeting, and enhanced therapeutic effectiveness [54,55]. Various types of NPs have been investigated for their therapeutic potential as nanocarriers for PSs in PDT (Table 2).

2.2.1 Liposome-based nanoparticles in PDT

Generally, liposome-based NPs have emerged as a promising drug delivery system in PDT due to their biocompatibility, controlled drug release, and ability to enhance the therapeutic efficacy of PSs [82]. First described by Alec Bangham in the 1960s, liposomes are spherical vesicles composed of phospholipid bilayers that can encapsulate both hydrophilic and hydrophobic drugs [83]. Their structural similarity to biological membranes makes them highly effective in improving the bioavailability and stability of PSs [84−86]. Compared to other nanocarriers such as polymeric NPs and dendrimers, liposomes offer reduced toxicity, enhanced circulation time, and improved tumor-targeting properties through surface modifications like PEGylation, ligand conjugation, and translational feasibility [87,88]. In addition, liposomes are naturally biodegradable and non-immunogenic due to their synthesis and design from natural or phospholipids, particularly when PEGylated [89]. However, depending on the byproducts of polymer breakdown or leftover solvents from manufacturing, polymeric NPs may be cytotoxic [90]. Multiple cationic surface charges carried by dendrimers, especially those of higher generations, have the ability to rupture cell membranes and cause dose-dependent cytotoxicity [91,92]. Likewise, FDA-approved liposome formulations such as Doxil® and AmBisome® have been around for a while, and there are proven manufacturing procedures for large-scale, good manufacturing practices-compliant production [19,93,94].

Despite their scalability, polymeric NPs frequently need organic solvents, surfactants, and more involved purification procedures [95,96]. Even with having a very consistent structure, dendrimers are made by a number of steps that are expensive, time-consuming, and challenging to scale [97]. Although surface modification with ligands (such as folate, transferrin, and antibodies) is supported by all three systems, liposomes offer a flexible bilayer surface that may be conjugated with ligands for active targeting and PEGylation for extended circulation [98]. While dendrimer targeting efficacy is frequently hindered by steric hindrance from densely packed surface groups, polymeric NPs may be changed similarly, albeit more difficultly [92,99]. In summary, liposomes have a dominating place in the current nanomedicine pipelines for PDT because they achieve a good balance between PDT effectiveness, biocompatibility, and clinical scalability. Nonetheless, each platform offers benefits that vary depending on the situation and may be used to achieve certain therapeutic objectives. Given these advantages, Table 3 summarizes the composition of liposomes commonly used in PDT.

In addition, the recent advances in nanotechnology has enabled the development of stimuli-responsive liposomal formulations, capable of releasing their payload in response to pH, temperature, or enzymatic activity, further optimizing PDT outcomes [110,111]. Numerous studies have demonstrated the potential of liposome-based nanoparticles in PDT, showing enhanced tumor accumulation, improved singlet oxygen generation, and increased phototoxicity against cancer cells. The diversity in liposome design also allows for the incorporation of various PSs, such as porphyrins (e.g., Photofrin, Foscan), phthalocyanines (e.g., ZnPc), chlorins (e.g., Ce6), and newer derivatives like BODIPY or porphycenes. These PSs are encapsulated or conjugated with liposomal membranes using different strategies such as passive loading, post-insertion, and solvent exchange methods to maximize their therapeutic efficacy. Hence, Table 4 summarized the composition and classification of liposomes used in PDT, highlighting critical parameters such as lipid composition, PS incorporation ratio, method of liposome preparation, particle size, cancer target, and key observations. Notably, liposomal formulations such as Visudyne® (BPD-MA), Foslip®, Fospeg® (mTHPC), and CGP55847® (ZnPc) have been explored in both preclinical and clinical settings, demonstrating significant potential for selective tumor ablation, enhanced bioavailability, and minimized side effects. The most commonly used lipids in nanotechnology include cholesterol (CHOL), dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylglycerol (DPPG), distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG), dioleoylphosphatidylserine (DOPS), egg phosphatidylglycerol (EPG), 1,2-dioleoyl-sn-glycero-3-ethylphosphocholine (EDOPC), and 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) [27]. These lipids are widely utilized in nanotechnology owing to their biocompatibility, structural adaptability, and capacity to form stable bilayer membranes. Such properties make them ideal for the formulation of liposomes, lipid nanoparticles, and other nanocarrier systems designed for targeted drug and gene delivery.

Meanwhile, Dragicevic-Curic and Fahr [115] reviewed the potential of liposomes as delivery systems in topical PDT, emphasizing that the major limitation of topical PDT is the inadequate penetration of photosensitizers into the skin, which confines its use to superficial lesions. They reported that recent studies have investigated various types of liposomes to encapsulate PSs such as 5-aminolevulinic acid (5-ALA), mTHPC, and methylene blue in order to enhance their skin penetration while minimizing systemic absorption and cytotoxicity. According to the authors, these liposomal formulations have shown improved delivery efficiency compared to free drugs, suggesting potential for treating deeper and hyperkeratotic skin lesions. They noted that despite these promising results, liposomes have not yet attracted sufficient attention in the field of topical PDT and stressed the need for more in vivo studies to establish their therapeutic effectiveness. The authors concluded that further research is essential to provide strong evidence supporting the clinical use of liposomal carriers in enhancing the efficacy and safety of topical PDT.

In the last ten years, numerous nanoscale drug delivery systems have been developed for use in PDT, generally falling into two categories i.e., organic or inorganic materials [116−118]. Building on conventional drug delivery strategies and addressing the hydrophobic nature of most PSs, researchers have predominantly utilized non-covalent encapsulation of PSs within organic nanocarriers such as liposomes, micelles, and polymer-based NPs [36,119]. In addition, PDT has been transformed in recent years by nanoengineered PS systems that improve ROS production efficiency, tumor targeting, stability, and solubility [89]. Liposomes continue to be one of the most extensively studied platforms because of its biocompatibility and ability to contain both hydrophilic and lipophilic PSs [1,89,120]. As highlighted by Lee and Thompson [121], for enhanced tumor selectivity and reduced off-target effects, liposomal PSs can be further functionalized with targeting ligands or stimuli-responsive moieties. Similarly, polymeric NPs, such as PEG-PLA or PLGA-based systems, offer tunable drug release kinetics and co-delivery potential.

Pallavi et al. [122] reported that despite the availability of various treatment options for cancer such as chemotherapy, radiotherapy, and surgical procedures, these conventional therapies suffer from non-specificity and often damage healthy cells along with malignant ones, leading to severe side effects. As a result, PDT has gained increasing attention as an alternative approach due to its ability to generate cytotoxic ROS in a targeted manner using a photosensitizer, molecular oxygen, and light in the visible to near-infrared (NIR) range. In their study, they investigated the use of rhodamine 6G (R6G), a light-sensitive laser dye, as a photosensitizer and addressed its limitations related to poor aqueous solubility and low ROS yield. They developed chitosan–alginate (Cs–Alg) blended polymeric nanoparticles at an optimal concentration of 160 mg/mL to encapsulate R6G, significantly enhancing its solubility and photodynamic efficiency. Spectrophotometric and fluorometric measurements showed a threefold increase in ROS quantum yield compared to R6G in aqueous solution. This was further validated through PDT experiments using human epithelial carcinoma cells, demonstrating improved therapeutic efficacy. The formulations also functioned as effective fluorescence-based optical contrast agents, as confirmed by phantom imaging with an IVIS imaging system. Zebrafish embryo assays were used to assess in vivo biocompatibility and confirmed the safety of the formulation. Additionally, drug release studies indicated that the release profile of R6G followed Non-Fickian kinetics, suggesting a combination of diffusion and polymer relaxation mechanisms. Based on these findings, Pallavi et al. concluded that the Cs–Alg NP formulation of R6G holds strong potential as a theranostic agent for PDT-mediated cancer therapy and fluorescence-guided diagnostics.

Based on a somewhat similar concept, Chota et al. [1] developed a liposome-based nanocomplex co-loaded with hydrophilic AgNPs and hydrophobic zinc phthalocyanine tetrasulfonate (ZnPcS₄) PS capable of co-localizing within vital cellular organelles and generating high levels of ROS post laser irradiation. Figure 2A showcased the preferential sub cellular accumulation or/ co-localization of the nanocomplex AgNPs-Lip@ZnPcS₄ within the endoplasmic reticulum, mitochondria, and lysosomes of MCF-7 breast cancer cells. In addition, AgNPs-Lip@ZnPcS₄ nanocomplex demonstrated significant cytotoxic effects and therapeutic potential against MCF-7 breast cells (Fig. 2B). This was primarily attributed to apoptosis induction using the 50% inhibitory concentration (IC₅₀) across all experimental models (Fig. 2C and D), driven by the loss of mitochondrial membrane potential (ΔΨm), release of cytochrome C and ROS generation (Fig. 2E−H), increased activities of Casp 8 and 9, and expression of pro-apoptotic proteins Bax and Bak (Fig. 3A−F). Considering the complexities of breast cancer prognosis, these findings highlight the potential of liposomal nanoformulations in enhancing PDT efficacy, emphasizing the need for further investigation in clinical applications.

Apart from the common AgNPs nanomaterial, AuNPs-based nanomaterials have also gained significant attention in PDT. As one of the most promising next-generation photosensitizers for PDT, AuNPs exhibit properties similar to those of AgNPs, making them highly effective in enhancing therapeutic outcomes, owing to their high surface area, and low toxicity, under laser light irradiation [123]. Notably Moloudi et al. [124] investigated a novel approach to PDT for lung cancer by developing a liposome-based nanocarrier co-loaded with berberine (BBR) and citrate gold nanoparticles (AuNPs), termed Lipo@AuNPs@BBR. The researchers first synthesized Lipo@AuNPs@BBR using the thin-film hydration method and the nanocomplex was later characterized using transmission electron microscopy confirmed a nanoparticle size of 100 nm, while energy-dispersive X-ray spectroscopy verified the successful co-loading of BBR and AuNPs onto liposomes (Fig. 4A). In addition, their study revealed that maximum loading capacity was achieved at 14 μM (14%) for BBR and 11 μg/mL (18.33%) for AuNPs. The study hypothesized that AuNPs could enhance the photodynamic effects of BBR, thereby improving treatment outcomes in A549 lung cancer spheroid cells. To assess therapeutic efficacy, the Lipo@AuNPs@BBR complex was tested at an IC₅₀ concentration of 80 μg/mL, combined with a 405 nm laser at 15 J/cm² fluency. The results from their study demonstrated significant increase in cytotoxicity, reducing A549 spheroid cell viability to 34.12% post-PDT (Fig. 4B−E). These findings suggest that Lipo@AuNPs@BBR is not only a promising PS for PDT but also a nanotheranostic agent with potential applications in tumor diagnosis and therapy for in vivo studies.

2.2.2 Lipid-based upconversion nanoparticles

Upconversion NPs (UCNPs) are a class of nanomaterials capable of converting low-energy light into higher-energy emissions through sequential multiphoton excitation, typically enabling the conversion of NIR light into visible or ultraviolet (UV) light [125]. This unique optical property such as their large surface area, adjustable pore size and surface characteristics has positioned them as powerful tools in biomedical applications such as imaging, phototherapy, and biosensing [126]. UCNPs generally consist of three components: a host matrix, activators, and sensitizers [127]. The host matrix makes up the majority of the NP and can include materials such as NaREF₄ (RE = rare earth), CaF₂, and Y₂O₃ [127,128]. Furthermore, RE elements exhibit high chemical and thermal stability, low phonon energy, excellent transparency, and minimal lattice stress [129,130].

Despite their promising optical properties, UCNPs often exhibit poor biocompatibility due to their inorganic composition, potential cytotoxicity, and limited stability in physiologic environments, which can hinder their direct application in biomedical settings [128]. To overcome the limitations associated with the poor biocompatibility and aqueous instability of UCNPs, these nanomaterials are increasingly being integrated into lipid-based delivery systems. This strategy has led to the development of lipid-coated UCNPs, a new class of hybrid nanocarriers that combine the unique optical properties of UCNPs with the enhanced biocompatibility, colloidal stability, and targeted delivery potential of lipid-based materials [131,132]. These hybrid systems allow for better dispersion in biological environments and facilitate multifunctional applications such as imaging-guided therapy and controlled drug release [133]. Over recent decades, UCNPs have attracted growing attention in the biomedical field, not only due to their ability to emit high-energy light under low-energy excitation but also because of their large surface area and tunable surface chemistry, which enable further functionalization for specific biomedical tasks.

For instance, Opoku-Damoah et al. [134] synthesized a lipid-encapsulated upconversion nanoparticle (UCNP)-based nanosystem for NIR light-mediated carbon monoxide (CO) release, aimed at advancing cancer gas therapy. Recognizing the therapeutic potential of gasotransmitters like CO, and despite the inherent challenges associated with their controlled delivery, the researchers engineered a photo-responsive platform incorporating carbon monoxide-releasing molecules (CORMs). The developed core-shell UCNPs were capable of converting low-energy, tissue-penetrating NIR light (808 or 980 nm) into UV light, which subsequently triggered CO release from the encapsulated CORMs. To enhance biocompatibility and cellular uptake, the nanoparticles were coated with a lipid layer. In vitro evaluations demonstrated efficient internalization of the nanoformulation by HCT116 colorectal cancer cells, with light-triggered, sustained CO release resulting in a dose-dependent cytotoxic effect. The therapeutic action was primarily attributed to intracellular CO-mediated ROS generation and the induction of apoptosis.

To further enhance the therapeutic specificity and efficacy of the lipid-encapsulated UCNP-based nanosystem, antibody functionalization could be employed. Conjugating tumor-specific antibodies to the surface of the lipid-coated UCNPs, the nanosystem can achieve targeted recognition and binding to cancer cell surface markers, thereby improving cellular uptake and minimizing off-target effects [135]. This targeted delivery approach would not only increase the accumulation of the therapeutic agents at the tumor site but also enhance the precision of PDT. When combined with the UCNPs’ ability to convert deeply penetrating NIR light into shorter wavelengths that activate PSs, antibody-functionalized platforms offer a promising strategy for more selective and potent treatment outcomes in cancer therapy.

Nanotheranostic-based photochemotherapies with targeted drug delivery have significantly advanced the field of cancer treatment. A study by Narendra et al. [136] developed a transferrin-conjugated theranostic liposomal system incorporating docetaxel (DXL) and UCNPs for targeted glioma diagnosis and therapy. Utilizing a solvent injection method, the researchers formulated liposomes designed to facilitate both imaging and treatment functions. The resulting nanocarriers exhibited a spherical morphology with an average particle size of approximately 200 nm. High encapsulation efficiency was achieved, reaching up to 75.93%, while in vitro drug release studies indicated a cumulative release of 71.10%, demonstrating sustained release properties. Elemental and fluorescence analyses confirmed the presence and functionality of UCNPs within the liposomes. Cytotoxicity assays performed on C6 glioma cells revealed that the transferrin-targeted liposomes exhibited significantly lower IC₅₀ values compared to non-targeted counterparts, indicating improved cellular uptake and enhanced anticancer activity. These findings suggest that the designed transferrin-conjugated UCNP-liposomes hold strong potential as a dual-function theranostic platform, warranting further preclinical investigation through in vitro and in vivo evaluations.

Subsequently, Khan et al. [137] developed a multifunctional injectable theranostic system by engineering polyethyleneimine-coated UCNPs covalently conjugated with doxorubicin (DOX). These UCNP-DOX complexes were incorporated with a synthesized epidermal growth factor receptor (EGFR)-targeting peptide and a polymer composite, then electrospun into nanofibers suitable for injectable dosage forms. The synthesized UCNPs had an average size of 26.75 ± 1.54 nm, while the resulting nanofibers exhibited a diameter of 162 ± 2.82 nm. Optimized dopant ratios enabled strong photoluminescence with maximum emission intensity near 800 nm upon 980 nm excitation. The paramagnetic properties of the UCNPs and successful amide linkage with DOX were confirmed through analytical techniques. The nanoformulation demonstrated a high doxorubicin loading capacity of 54.56% within the UCNPs and 98.74% encapsulation efficiency in the nanofiber matrix. Drug release studies revealed a sustained and pH-responsive release profile, with increased release under acidic conditions, which is favorable for targeting the TME. Additionally, the nanofibers showed robust mechanical strength, effective swelling behavior, and a desirable degradation profile. Biocompatibility assessments indicated over 90% cell viability in L929 and NIH/3T3 fibroblast cell lines, while the formulation exhibited notable cytotoxicity against cancer cells, with IC₅₀ values of 2.15 ± 0.54 µg/mL for MDA-MB-231, 2.87 ± 0.67 µg/mL for 4T1, and 3.42 ± 0.45 µg/mL for MCF-7 cells. Upon 980 nm laser irradiation at a power density of 0.5 W/cm², the UCNPs generated a temperature rise of approximately 62.7°C within 5 min, supporting an additional photothermal therapeutic effect. Moreover, the nanoformulation induced significant ROS production (65.67% ± 3.21%) and triggered apoptosis via cell cycle arrest at the sub-G1 phase, highlighting the potential of this nanoplatform for efficient and targeted breast cancer therapy.

In addition, clinicians can visualize tumor sites, track nanoparticle distribution, and assess treatment efficacy in real time. Lipid-based coatings, particularly in systems utilizing UCNPs, further enhance cellular uptake and minimize systemic toxicity. When combined with PSs and encapsulated in biocompatible carriers such as liposomes, these nanoplatforms offer simultaneous tumor targeting and light-triggered therapeutic activation [123,138,139]. This dual-functionality not only increases treatment specificity and minimizes off-target effects but also enables dynamic monitoring, thereby supporting more personalized and adaptive cancer therapy.

A review by Tang et al. [140] focused on the advancements in lipid-based NPs (LNPs) for cancer theranostics. The study discussed how LNPs have been engineered to deliver both imaging agents and therapeutics simultaneously, enabling real-time monitoring of treatment efficacy. The versatility and adaptability of LNPs make them suitable platforms for integrated cancer diagnosis and therapy. In line with this, Prasad et al. [141] developed liposomal nanotheranostics encapsulating AuNPs, graphene quantum dots (GQDs), and a chemotherapeutic agent. The liposomes were surface-functionalized with folic acid to target tumor cells. This formulation demonstrated site-specific tumor diagnosis and photo-triggered tumor ablation. Enhanced cellular uptake, prolonged tumor retention, and significant imaging and therapeutic efficacy were observed, indicating the potential of such liposomal systems in cancer theranostics. In their study, the authors reported the development of a NIR light-triggered approach designed to enhance the accumulation of NFGL-based nanotheranostic agents in 4T1 breast tumor-bearing mouse models. They indicated that folic acid-conjugated NFGL (NFGL–FA) functioned effectively as a safe multimodal contrast agent for localized tumor imaging via both X-ray computed tomography (CT) and NIR fluorescence (NIRF) modalities. According to the report, following two weeks of tumor development, a single subcutaneous dose (100 µL) of the nanohybrid formulation was administered directly to the tumor site. 1 h after the injection, the tumor area was exposed to NIR light (750 nm, 1 W/cm²) for 10 min, and subsequent imaging was conducted. The researchers observed that animals treated with NIR light exhibited notably higher brightness and contrast in tumor regions on X-ray CT images compared to control groups, including those that were untreated or pre-injected. This enhanced contrast persisted up to 48 h post-injection, suggesting a strong retention and accumulation capacity of the liposome-based nanocontrast agents. Additionally, these findings were supported by NIRF imaging, which revealed a significantly stronger emission intensity from NIR-exposed tumor regions relative to non-treated groups (Fig. 5A−D).

Likewise, the authors investigated site-specific tumor imaging and biodistribution at different time points (1, 24, and 48 h) following intravenous administration of NFGL–FA in tumor-bearing mice, using a single dose of 100 µL at a concentration of 10 mg/kg bodyweight. They reported that the peak fluorescence emission from the tumor site was observed at 24 h post-injection, indicating maximum accumulation of the nanohybrids within the TME. This elevated signal remained prominent up to 48 h, which the authors attributed to the strong binding affinity of the NFGL–FA formulation (Fig. 5E). Furthermore, biodistribution analysis performed 48 h after injection revealed fluorescence signals in major organs, including the heart, lungs, liver, kidneys, spleen, and intestine, as well as the tumor itself, confirming the systemic distribution and tumor-targeting capability of the nanohybrids (Fig. 5F).

2.2.3 Stimuli-responsive liposomal systems in PDT

Liposomes are increasingly engineered into innovative drug delivery platforms by encapsulating anticancer agents for targeted, often implantable, administration. To enhance delivery of poorly water-soluble chemotherapeutics, such nanoparticles are further embedded within appropriate biomaterials such as PLGA, PCL, or chitosan to create sustained-release implants that maintain therapeutic drug levels at the tumor site [142]. Optimizing physicochemical attributes like surface functionalization (e.g., PEGylation, ligand conjugation) and precise particle sizing enhances tumor targeting through passive (EPR effect) and active mechanisms, significantly improving efficacy in cancer therapy. The therapeutic potential of these systems has been evaluated using in vitro tumor cell models to replicate the TME, thus allowing dynamic assessment of anticancer effectiveness prior to in vivo studies.

Ibrahim et al. [143] demonstrated the development of a novel oral nanoparticle drug delivery system designed for colon-specific release of chemotherapeutic agents 5-fluorouracil (5-FU) and leucovorin (LV), commonly used in the treatment of large bowel malignancies such as colon cancer and colorectal carcinoma. Utilizing a modified double-emulsion solvent evaporation method, the researchers formulated pH-responsive Eudragit® S100 polymeric nanoparticles encapsulating the 5-FU/LV combination. The resulting nanoparticles exhibited distinct pH-sensitive behavior, allowing minimal drug release at acidic pH and enhanced release at colonic pH levels, thus ensuring targeted delivery. In vitro experiments demonstrated that these drug-loaded nanoparticles induced significantly greater cytotoxic effects in colon cancer cell lines compared to the administration of free drugs. These promising preclinical outcomes support the potential progression of this formulation toward clinical trials for nanoparticle-mediated treatment of colon malignancies.

Rajesh et al. [144] developed an innovative pH-responsive nanostructured lipid nanoparticle (LNP) system designed to enhance the delivery and controlled release of SN-38, a highly potent chemotherapeutic agent known to be 1000 times more efficacious than its prodrug, irinotecan. However, SN-38’s poor aqueous solubility and instability at physiologic pH have limited its clinical application. To address these limitations, the researchers synthesized four novel aminolipids and incorporated them into monoolein (MO)-based LNPs. These systems exhibited a pH-induced structural transition, shifting from a slow-releasing hexagonal phase (H₂) at physiologic pH to a fast-releasing bicontinuous cubic phase (Q₂) under acidic tumor-like conditions (pH 5.5–7.0), as confirmed through small-angle X-ray scattering (SAXS). Among the four formulations tested, those containing N-(Pyridin-4-ylmethyl) oleamide (OAPy-4) or N-(2(piperidin-1yl)ethyl) oleamide (OAPi-1) showed the most responsive phase transitions under tumor-relevant pH conditions. SN-38 was effectively encapsulated within MO/OAPy-4 LNPs, achieving ~100-fold increase in aqueous solubility compared to the pure drug. Furthermore, in vitro release studies revealed significantly faster drug release at acidic pH (pH 5) compared to neutral pH (7.4), supporting the potential of these LNPs for tumor-specific drug release. The study underscores the capability of pH-responsive LNPs to enhance the solubility, stability, and selective release of SN-38, paving the way for its application in targeted cancer therapy.

Teixeira et al. [145] developed and optimized pH-responsive lyotropic non-lamellar liquid crystalline (LNLC) nanoassemblies for enhanced and selective delivery of doxorubicin (DOX) in cancer therapy. Recognizing the need for drug carriers with improved efficacy and specificity, the researchers engineered hybrid polymeric-lipid LNLCs capable of releasing DOX preferentially in acidic environments typical of the TME and intracellular vesicles (pH 5.5), while maintaining minimal drug release at physiologic pH (7.5). This behavior suggests a significant potential for reducing cytotoxic effects in healthy tissues. The LNLCs demonstrated high drug encapsulation efficiency (> 90%), substantial drug loading (> 7%), and excellent colloidal stability over four weeks. Cellular uptake studies using confocal microscopy revealed that DOX-loaded LNLCs accumulated near the nucleus of HepG2 liver cancer cells, with clear signs of apoptosis. In vitro cytotoxicity assays further confirmed that DOX-loaded LNLCs induced greater cell death in cancer cell lines (MDA-MB-231, HepG2 after 24 h; NCI-H1299 after 48 h) compared to the free drug. Importantly, free DOX exhibited greater toxicity to normal cells than the LNLC formulations, underscoring the safety advantage of the nanoassemblies. These findings support the therapeutic promise of DOX-loaded LNLCs as intelligent, stimuli-responsive drug delivery platforms for targeted cancer treatment. Taken together, these studies collectively illustrate how pH-responsive liposomal and lipid nanoparticle systems are being effectively designed to improve stability at physiologic conditions, trigger drug release in acidic TME, and significantly enhance therapeutic efficacy across various cancer models.

2.3 Combination therapies

2.3.1 PDT with chemotherapy and immunotherapy

Additional work is required to develop and improve the photophysical, photochemical and stability of different forms of PSs used in cancer PDT. Several issues must be addressed before it may be utilized in clinical studies. Likewise, several PSs and PDT-based therapeutic modalities are now significantly increasing the safety and efficacy of cancer PDT [52]. Like any other therapy, PDT has its own advantages and disadvantages. Examples of the major advantages of PDT include active targeting, minimally invasive, repeatable, fewer long-term side effects, potential for combination therapies and cost-effectiveness and convenience [146,147]. On the other side, some of the disadvantages of PDT include limited penetration of light into deeper tissues, skin side effects, and possibility of cancer recurrences [147−149]. As a result, combinatorial and multimodal platforms are probably good options to increase the efficacy of PDT for cancer.

With efforts to address some of the limitations associated with PDT, Meng et al. [150] developed a strategy of combining PDT with immunotherapy and chemotherapy in the treatment of gastric cancer. They further demonstrated that the liposomal nanocomplex PTX-R837-IR820@TSL was actively targeting tumor cells, good stability and superior photothermal-mediated drug release properties. More interestingly, the synthesized PTX-R837-IR820@TSL was reported to localize within the cytoplasm. In addition, the nanocomplex PTX-R837-IR820@TSL was irradiated using an 808 nm laser and the levels of singlet oxygen was confirmed. Furthermore, post-irradiation, the nanocomplex PTX-R837-IR820@TSL generated singlet oxygen induced significant cytotoxicity which was also attributed to PTT effects.

In the same context, Peng et al. [151] developed a long-circulating dual-loaded PEGylated liposomal nanocomplex co-encapsulated with platinum-based chemotherapeutic drug, chlorin e6, and cisplatin. Their study demonstrated that tumor distribution of accessible chemotherapeutic drugs encapsulated in liposomes might be enhanced while minimizing exposure to healthy organs by combining a single dosage of dual-effect liposomes with an ideal lighting scheme. In their study, they further suggest that the two primary causes of total tumor eradication could be due to vascular damage and increase in concentration of the chemotherapeutic drug.

Combining PDT with immunotherapy shows promise as a cancer treatment strategy. PDT can directly kill tumor cells and trigger an immune response, while immunotherapy aims to enhance the body’s natural defenses against cancer [152]. Combining these two approaches can potentially lead to a synergistic effect, improving treatment outcomes for various cancers. In addition, there are different types of immunotherapeutic drugs used in the treatment of various cancers. These drugs can be classified based on the mechanism of action e.g., cytokines, CART-cell therapy, immune checkpoint inhibitors, monoclonal antibodies, and immunomodulators.

To evaluate the combination efficiency of chemotherapy and PDT, He et al. [153] designed a nanoscale core-shell polymeric nanocomplex loaded with a PS pyropheophorbide-lipid conjugate in the shell. When combined with immunotherapeutic PD-L1 checkpoint blockade, the polymeric nanocomplex displayed cellular regression in both irradiated and non-irradiated tumors, thereby initiating significant tumor-specific immune response. Using immunofluorescence assay, the antitumor immune response triggered by chemotherapy and PDT of NCP@pyrolipid in conjunction with anti-PD-L1 was further validated. While no tumor-infiltrating TCR β + cells were seen in PBS-treated animals, we discovered that NCP@pyrolipid combined with light-irradiation and anti-PD-L1 therapy induced TCR β + cell infiltration inside both primary and distant tumor tissues.

In addition, another study by Reginato et al. [154] the authors postulated whether PDT can induce the development of antigen-specific immune response, and if PDT-mediated immune response can be initiated via the depletion of T regulatory cell (Treg). Additionally, they also investigated into whether the combinational effects both cyclophosphamide (CY) and PDT can promote the immunity against wild type tumors that express the self-antigen (gp70). They found that the combination of CY and PDT led to the complete tumor regression in ~90% of treated mice. Furthermore, they observed a decrease in the levels of Treg post-combination therapy. Lastly, the researchers observed a comparable decrease in the levels of TGF-β to that of naïve mice.

2.3.2 PDT with sonodynamic and photothermal therapy

Monotherapy, using a single drug to kill cancer cells, remains important in cancer treatment and benefits many patients, but challenges such as drug resistance and adverse side effects persist. Combining two or more agents to target different aspects of tumor growth has therefore emerged as a promising strategy [155,156]. Combination therapy can better target multiple cancer cell types by tackling tumor complexity and heterogeneity [155]. It can also help prevent or delay the development of drug resistance and may enhance treatment efficacy, thus resulting in deeper and more durable responses compared to monotherapy [157−159]. Despite these advantages, progress with combination therapies has often been incremental, typically involving the addition of new agents to existing regimens rather than fully optimized multi-target approaches.

As aforementioned, like other therapies, PDT offers several intrinsic advantages, including specific tumor targeting, minimally invasive application, repeatability, low systemic toxicity, compatibility with multimodal therapeutic regimens, and cost-effectiveness [160−162]. Nevertheless, PDT is constrained by inherent limitations such as limited light penetration in deep-seated tumors, tumor hypoxia, suboptimal ROS generation, photosensitivity of the skin, and the risk of tumor recurrence [163−165]. These challenges can be effectively mitigated through combinatorial strategies with sonodynamic therapy (SDT) and photothermal therapy (PTT). The integration of SDT with PDT allows the use of ultrasound, which penetrates deep into tissues and activates sonosensitizers to generate ROS even in hypoxic tumor regions, while cavitation effects improve local oxygen availability and enhance cytotoxicity [166−168]. Concurrently, PTT utilizes near-infrared-responsive photothermal agents to induce localized hyperthermia, which improves tumor perfusion, and contributes additional thermal cytotoxicity [169,170]. In tri-modal platforms, commonly employed agents such as indocyanine green (ICG) and UCNPs serve as both PS’s and photothermal transducers, thereby enabling synergistic ROS production, efficient energy conversion, and deep-tissue penetration [171−173]. Collectively, PDT combined with SDT and PTT establishes a mechanistically complementary and highly effective therapeutic framework that addresses the limitations of conventional PDT and significantly improves anticancer efficacy in solid tumors.

Conceptually, Fig. 6 depicts a multimodal combination therapy technique that incorporates PTT, PDT, and SDT to improve cancer treatment. After intravenous delivery, liposome-based NPs preferentially localize at the tumor site and are selectively triggered by external stimuli (i.e., laser). NIR laser irradiation causes the PS/NPs to transition from the ground state to higher singlet states, resulting in non-radiative energy dissipation and localized heat generation, which promotes PTT-induced hyperthermia and direct tumor cell destruction. ISC to the T₁ state allows PDT through both Type II reactions, producing cytotoxic ¹O₂, and Type I reactions, generating reactive radical species such as O₂^•–, OH^•, and H₂O₂, resulting in oxidative damage to cellular organelles and biomolecules. Concurrently, ultrasonic activation causes SDT through acoustic cavitation and electron transfer mechanisms, creating more ROS even under hypoxic condition and increasing cellular permeability and intracellular drug release. Thermal ablation, oxidative stress, and mechanical disruption work together to cause synergistic tumor cell apoptosis and necrosis, overcoming the limitations of individual treatment modalities and eventually leading to effective tumor regression and long-term therapeutic efficacy.

Consistent with this perspective, Borah et al. [174] reported a multimodality therapeutic platform demonstrating that SDT combined with PDT achieves enhanced and durable tumor control in a brain tumor model. Using U87 patient-derived xenograft tumors implanted subcutaneously in SCID mice, the authors showed for the first time that SDT and PDT induce cancer cell death through distinct mechanistic pathways. Upon ultrasound exposure after 24 h incubation with the photosensitizer HPPH [3-(1′-hexyloxy)ethyl-3-devinyl-pyropheophorbide-a], SDT primarily proceeds via Type I reactions, generating radicals and radical ions through electron-transfer processes, whereas PDT predominantly relies on Type II reactions mediated by highly reactive singlet oxygen. Both in vitro and in vivo experiments demonstrated that the combined SDT–PDT approach significantly improved tumor cell killing compared with either modality alone, suggesting additive or synergistic therapeutic effects. Furthermore, tumor delivery of HPPH was enhanced using cationic polyacrylamide nanoparticles, with ultrasound exposure triggering photosensitizer release. Vascular disruption induced by the combination therapy was confirmed through dynamic contrast-enhanced imaging with HSA-Gd(III)DTPA, highlighting the strong impact of this dual-modality strategy on tumor vasculature and long-term treatment efficacy.

Another study by Ghorbani et al. [175] investigated the synergistic anticancer effects of combining PDT and PTT on HeLa cells using gold-gold sulfide (GGS) nanoshells coupled with indocyanine green (ICG). The authors identified PDT and PTT as recognized ocular cancer therapy techniques, noting that PTT is particularly adaptable to conjunction with other treatments. They identified restricted light penetration in biological tissues as a significant problem for optical treatments, emphasizing the benefits of NIR-absorbing agents, which allow for deeper tissue penetration. In this particular instance, ICG was utilized as a photosensitizer and gold nanostructures as PTT agents, with GGS nanoshells having dual absorption peaks in the visible and NIR bands. The study sought to assess the possible synergistic effects of combined PDT and PTT using GGS-ICG conjugates. According to their findings, laser irradiation alone and in the presence of GGS did not cause considerable cytotoxicity. The maximal cell death rates were 15 ± 7% for GGS, 50 ± 3% for ICG, and 31 ± 3% for the GGS-ICG compound. The study found a substantial difference in the cytotoxic effects of ICG and GGS-ICG at energy densities over 2250 J/cm², suggesting a potential interaction between photodynamic and photothermal processes under higher irradiation circumstances.

To overcome drug efflux-mediated resistance and increase intracellular accumulation in tumor cells, targeting P-glycoprotein (P-gp), a membrane transporter encoded by the MDR1 gene, has emerged as a promising method. In this context, Li et al. [176] designed and synthesized ICG&Cur@MoS₂ NPs. This formulation achieves the combinatorial action of PTT-PDT and effectively inhibits the P-gp protein. The MDR1 gene encodes P-gp, a membrane protein found at the ATP-dependent efflux pump in different cancer cells. This pump can develop multidrug resistance (MDR) by removing anticancer medicines from the cell, therefore inhibiting P-gp activities and boosting the PDT efficiency. Additionally, it is worth noting that the synergistic combination of PTT/SDT with anti-PD-1 can enhance tumor suppression. More interestingly, Lin et al. [166] demonstrated that CHINPs-augmented PTT/SDT successfully eradicated primary tumors while also triggering an anti-tumor immune response. This result was achieved by generating tumor fragments that released antigens, allowing PD-1 inhibition to limit tumor spread. The synergistic treatment effectiveness was studied using an orthotopic 4T1 bilateral tumor model.

2.4 Clinical translation and approved liposomal PDT agents

The development of liposomal formulations that improve pharmacokinetics, decrease off-target effects, and boost drug transport has greatly enhanced the clinical translation of PDT [177]. Liposomes have become successful clinical carriers for PSs because of their high biocompatibility and ability to contain both hydrophilic and hydrophobic drugs [24,177]. Visudyne®, a liposomal benzoporphyrin derivative that has FDA approval for the treatment of age-related macular degeneration, is one of the well-known liposomal PDT medicines [178−180]. Despite being mostly utilized in ophthalmology, Visudyne’s success showed that liposomal systems might be employed in PDT, which prompted more research in cancer [181,182]. Liposomal formulations of porphyrins, chlorins, and phthalocyanines that target a variety of tumors, such as pancreatic, prostate, and head and neck cancers, are undergoing clinical studies. Through the increased EPR effect, liposomes can boost tumor accumulation while reducing systemic toxicity. The general acceptance of liposomal PDT medicines in cancer is still hampered by issues such tumor heterogeneity, low light penetration, and immune suppression in the TME, despite encouraging preclinical results [36,181,182]. However, there is a lot of promise for next-generation cancer treatments when liposomal PDT is combined with immunotherapy and nanotechnology.

2.4.1 Biosafety and pharmacokinetic of nanomaterials in PDT

Thorough assessment of biocompatibility, biodistribution, clearance, and toxicity is crucial for the clinical translation of nanomaterials in photodynamic treatment. Particle size, surface charge, lipid composition, and PEGylation status, for instance, all affect the controlled pharmacokinetics of liposomal nanocarriers. In addition, in vivo biodistribution studies consistently show extended circulation times and eventual accumulation in the liver and spleen via the reticuloendothelial system (RES) [183−185]. While bigger Au nanorods or spheres tend to be retained in RES organs and might cause temporary oxidative or inflammatory responses that go away over time, ultra-small AuNPs clusters (~4–13 nm) exhibit effective renal clearance and little long-term accumulation [186,187]. Size-dependent pharmacokinetic profiles of PEGylated AuNPs further underscore the critical role of NP dimensions in determining clearance kinetics [183−187]. Mechanistically, poorly prepared metallic and silica-based nanocarriers have been shown to cause oxidative stress, DNA damage, and mitochondrial dysfunction; these effects are significantly lessened by surface functionalization (e.g., PEGylation or neutralizing ligand coatings) [188,189]. To guarantee safe and efficient PDT administration, clinical translation necessitates strong in vivo pharmacokinetics and biosafety profiles, including long-term toxicity testing, immunogenicity evaluations, and organ-specific accumulation investigations.

2.5 Limitations and future perspectives of liposomes in cancer PDT

The full therapeutic potential of liposomal-PDT is impeded by a number of current constraints. The early release or breakdown of PSs in the circulation is a significant problem as it decreases therapeutic effectiveness and increases off-target effects [190]. In summary, after being injected intravenously into the bloodstream, liposomes are easily absorbed by the reticuloendothelial system. More interestingly, opsonin’s identification of the liposomes as foreign substances encourages the mononuclear phagocyte system to phagocytically destroy them, which is a crucial factor affecting the liposomes’ duration and circulation [191]. Furthermore, low accumulation in deep tumor tissues and poor tumor penetration as a result of the variability of the increased EPR effect continue to be significant obstacles [192]. Under physiologic settings, liposomes may also show instability, which would shorten their circulation length [22]. Therefore, the synthesis of PEGylated stimuli-responsive liposomes, which release their payloads in response to tumor-specific factors like pH, enzymes, or light, is being investigated by researchers in an effort to get around the above-mentioned limitations. Targeting ligands like peptides or antibodies can also be added to the surface of the liposomes to improve their cellular uptake and tumor selectivity. Additionally, combining liposomal-PDT with other modalities like as immunotherapy or chemotherapy and incorporating imaging agents may also enhance treatment outcome and enable real-time therapeutic response monitoring.

3 Conclusions

This review highlights recent advancements in liposomal nanotechnology that have significantly improved the efficacy of PDT for cancer treatment. Liposome-based nanocarriers offer controlled drug release, enhanced tumor targeting, and reduced systemic toxicity, addressing key limitations of conventional photosensitizers. These nanosystems, typically 1–100 nm in size, provide high surface area for increased drug loading, protect therapeutic agents from premature degradation, and promote accumulation within tumors via the enhanced permeability and retention effect. Functionalization with targeting ligands or responsive elements further improves specificity and therapeutic precision. Recent developments have also led to multifunctional liposomal platforms capable of integrating imaging agents, chemotherapeutics, and targeting molecules for simultaneous diagnosis and therapy. Importantly, regulating ROS generation while ensuring targeted delivery remains critical to advancing PDT outcomes. Looking ahead, the integration of Machine Learning and Artificial Intelligence presents a promising direction, enabling data-driven optimization of nanoparticle design, prediction of biological interactions, and customization of PDT protocols based on patient-specific tumor characteristics [193,194]. AI-assisted image analysis also enhances real-time monitoring and treatment precision [194,195]. Together, the convergence of liposomal nanocarriers, advanced materials, and intelligent computational tools holds transformative potential for developing safer, more effective, and personalized PDT-based cancer therapies.

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