Photodynamic therapy meets nanotechnology: A synergistic approach for cancer treatment

Highlights

• •PDT is a non-invasive therapy using light-activated PS to induce cell death in various cancers.
• •Nanocarriers can improve PS solubility and targeting, while nanomaterials enhance photostability as alternative PSs.
• •Nanocarriers facilitate the co-delivery of PS and chemotherapy drugs, while targeting ligands enhance tumor specificity through the EPR effect.

Abstract

Over the years, significant progress has been made in treating fatal diseases, but cancer treatment is still a challenge. Photodynamic therapy, is a treatment that relies on photosensitization to target and destroy neoplastic cells. It has gained recognition as an effective treatment approach because of its precision, minimally invasive nature, and ability to stimulate the immune system, with applications spanning various medical fields such as oncology, dermatology, immunology, and ophthalmology. It works by activating a photosensitizing agent with a particular wavelength in the presence of oxygen, generating reactive oxygen species that trigger cell death. This oxygen-dependent treatment selectively targets cancer cells while minimizing adverse effects on healthy tissues, making it a promising approach in modern medicine. However, despite its therapeutic potential, PDT has limitations such as restricted light penetration and insufficient cellular uptake of photosensitizers by cancer cells. These challenges can be addressed through nanotechnology by optimizing photosensitizer formulations and modifying therapeutic strategies to enhance treatment efficacy. The incorporation of nanotechnology into photodynamic therapy has been particularly impactful, with nanomaterials serving as efficient carriers as well as photosensitizers. Engineered nanoparticles enable the direct delivery of therapeutic agents to tumors, enhancing specificity while minimizing side effects. This combined approach of photodynamic therapy-nanotechnology allows for effective treatment of different types of cancers, including resistant tumors and one’s which are hard-to-reach, by targeting specific cell markers and improving drug accumulation in various tumor environments. This review aims to highlight the importance of the use of nanotechnology in photodynamic therapy to treat various types of cancer in achieving desirable therapeutic effects.

Graphical abstract

Introduction

Cancer continues to be a major global health challenge despite significant advances in treatment [1]. Conventional therapies like chemotherapy and radiotherapy are associated with side effects such as pain, recurrence, and reduced quality of life. Photodynamic therapy (PDT), a non-invasive treatment used for cancer and certain non-infectious diseases [2], offers a promising alternative [3]. PDT has shown effectiveness against various cancers, including skin, lung, breast, prostate, pancreas, and brain tumors. It involves the administration of a drug or prodrug, typically a photosensitizing agent (PS), which is activated by light of specific wavelengths (620–690 nm) in the presence of oxygen, inducing cell death through necrosis or apoptosis [2]. This process occurs via photobiological (light–biological system interaction) and photochemical (light-induced chemical reactions) pathways. Light sources used vary, including visible, UV, and near-infrared (NIR) light, depending on the tumor type. PDT can be applied alone or in combination with other treatments such as surgery, radiation therapy, chemotherapy, hormone therapy, gene therapy, and immunotherapy to enhance therapeutic outcomes [4]. However, its clinical application remains limited due to the poor solubility of PSs, high cost, limited light penetration, oxygen dependence, and poor tumor selectivity [5].

To address these limitations, nanotechnology has emerged as a valuable tool for enhancing PDT. Nanocarriers improve PS solubility, targeting, and delivery, increasing the overall effectiveness of the therapy. First-generation PSs like photofrin and hematoporphyrin derivative (HpD) were associated with severe side effects, while second-generation agents such as aminolevulinic acid (ALA), its derivatives, and phthalocyanine compounds demonstrate improved safety profiles [6]. PSs can be incorporated into various nanoformulations including dendrimers, liposomes, solid lipid nanoparticles (NPs), polymeric NPs, gold NPs, and hydrogels to enhance their properties. Recent research has explored the use of molybdenum oxide, titanium dioxide (TiO₂), zinc oxide (ZnO), and tungsten oxide (WO₃)-based NPs as potential PSs in PDT [7]. Nanomaterials also serve as diagnostic and imaging agents [8] and can co-deliver PSs with chemotherapeutics. They offer advantages like low toxicity, biodegradability, improved photostability, tumor-specific targeting via ligands, and enhanced accumulation through the enhanced permeation and retention (EPR) effect [9].

Despite facing challenges in current cancer conditions, ongoing advancements in nanotechnology promises to make PDT more accessible, safe, and powerful therapeutic option for various kinds of cancers which is the focus of this review. Unlike previous reviews that focus on a single cancer type or broadly cover nanomedicine, this review highlights how nanotechnology can enhance PDT and addresses the specific delivery challenges across different cancers to support future clinical use.

Mechanism of PDT

PDT uses three components: PS, light and endogenous oxygen, all of which are nontoxic individually and act simultaneously. When activated by light, reactions occur leading to reactive oxygen species (ROS) formation. The PS accumulates in the tumor tissue, and upon irradiation with light of a specific wavelength, singlet oxygen is generated, inducing photodamage through direct tumor cell killing, vascular damage, and immune responses such as inflammatory reactions in the host [10]. PDT involves a standard drug dosage, a light source, and a specific drug-light interval (DLI) [11]. The extent of photodamage depends on PS concentration, localization, DLI, tumor type, and oxygen levels [12].

Upon light activation, two reactions occur - Type 1 and Type 2. In the Type 1 reaction, the excited triplet state PS transfers hydrogen atoms or electrons to biological molecules like lipids, nucleic acids (NA), and proteins, forming free radicals and ROS such as superoxide anion, hydrogen peroxide, and hydroxyl radicals. In the Type 2 reaction, the PS reacts with triplet oxygen to produce singlet oxygen via triplet-triplet annihilation [11]. Passive targeting via the EPR effect and NP surface modifications enhance PS delivery [13].

Brain cancer

Glioblastoma or glioblastoma multiforme (GBM) is one of the most challenging brain cancers to treat due to its aggressive, metastatic, and invasive nature, leading to poor prognosis. Genetic heterogeneity in GBM cells also enables adaptation to ROS. Traditional treatments such as surgery, chemotherapy, and radiotherapy often fail to provide long-term results, as GBM frequently recurs. A major limitation is the poor penetration of therapeutic agents across the blood-brain barrier (BBB) (Fig. 1D) [14]. Although nanomaterials have been minimally applied in crossing the BBB due to light penetration issues, near-infrared (NIR) light offers deeper tissue penetration with minimal damage to healthy tissue. Nanocarriers can cross the BBB via receptor-mediated endocytosis (RMT) or adsorption-mediated transcytosis (AMT) [15].

Fig. 1.

A. Cationic IR-780-loaded liposomes (ILs) for enhanced glioblastoma treatment via convection-enhanced delivery (CED) and NIR-assisted photothermal/PDT [29]. B. Representative single-slice images of ectopic U87 tumors, before and after PDT therapy, were acquired with Power Doppler, showing the vasculature with blood flow (red) and the tumor area (yellow line) [25]. C. In vivo post-PDT inflammation. (a) Rats treated by PDT after intravenous injection of AGuIX@PS@KDKPPR nanoparticles (1.75 μmol·kg⁻¹ porphyrin equivalent) and followed by MRI analysis via T2 anatomical and diffusion (DWI—diffusion-weighted imaging) sequences. (b) Macrophage infiltration, demonstrated by immunofluorescence [16] D. Illustration of active BBB penetration and the photothermal/photodynamic therapeutic design of ANG-IMNPs in an orthotopic glioblastoma tumor model [14]. E. Cell survival on macrophages post-PDT. AGuIX@PS@KDKPPR nanoparticles (NPs, 1 µM) were incubated with M0, M1, and M2 macrophages for 24 h (group “NPs + PDT”) [16].

For improved PDT effectiveness in GBM, Gadolinium (Gd)-based theranostic NP (AGuIX) functionalized with Lys-Asp-Lys-Pro-Pro-Arg (KDKPPR) peptides have been used to target Neuropilin-1 (NRP-1), overexpressed in GBM. PDT using these NPs activates M1 macrophages and suppresses M2 phenotypes, promoting antitumor and proinflammatory properties (Fig. 1C and 1E) [16]. Lanthanum-doped, mesoporous silica-coated, Gd-doped upconversion NP (UCNPs) also enable imaging and deeper light absorption in tumors [14]. Gold NP (AuNP) are effective carriers for hydrophobic drugs, capable of crossing the BBB and improved through PEGylation or peptide functionalization. Targeted delivery of Pc 4 using epidermal growth factor peptide-tagged AuNP (EGFpep-AuNP) resulted in prolonged retention at tumor sites and improved lysosomal drug delivery, reducing the required dosage [17]. In vivo, EGFpep-AuNP-Pc 4 altered biodistribution, enabling eventual AuNP elimination via EGFR localization [18]. Dual targeting AuNPs with EGFpep and transferrin peptide (Tfpep) further enhanced Pc 4 uptake and GBM cell death, outperforming monotargeted systems [6].

Polymeric NPs such as chitosan NP, poly d,l-lactide-co-glycolide (PLGA), polyacrylamide (PAA), silica, or ormosil NP, and dendrimers are used to load PSs for targeted delivery [16]. Kang et al., 2019 evaluated PS@chol-BSA NPs (cholesteryl bovine serum albumin) in U87MG GBM cells using triphenyl phosphonium-pheophorbide a (TPP-PheoA) conjugates with folate surface molecules to target folate receptors. These NPs showed high mitochondrial accumulation and improved anticancer efficacy [19,20]. Multifunctional Gd-based peptide-conjugated hybrid silica NPs combining chlorin PS, NRP-1-targeting peptides, and Gd chelated by 1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) derivatives showed specific intratumoral retention and magnetic resonance imaging (MRI) contrast enhancement in GBM-bearing rats [21]. PDT combined with metabolic, functional, and anatomical imaging may significantly advance brain tumor therapy [22].

In a study by Wen et al., 2025, hexagonal boron nitride NPs (BN NPs) were functionalized with Chlorin e6 (Ce6), coated with polyglycerol (PG), and loaded with DOX to form BNPD-Ce6@NE. Neutrophils (NE) served as carriers, enabling BBB crossing. Upon 808 nm laser exposure, rapid release of BNPD-Ce6 occurred, enhancing ROS generation and cytotoxicity [23].

Porphyrin-based PSs like meso tetraphenylporphyrin (TPP), due to their poor water solubility, are incorporated into Gadolinium-based theranostic NPs (AGuIX NPs) labelled with ⁶⁴Cu. AGuIX-TPP targets NRP-1 and can be modified with Terbium (Tb) to function as nanoscintillators and radiosensitizers, increasing ROS production under X-ray and arresting GBM cell growth (Fig. 1B) [24,25]. Metalated porphyrin-doped conjugated polymer NP (CPN) showed promising ROS generation, although resistance in T98G cells highlighted GBM heterogeneity [26].

Another type of NP that can be a potential PS is metalated porphyrin-doped conjugated polymer NP (CPN) because of their enhanced photostability and light absorption and have an efficient photosensitized formation of ROS. T98G cells had significantly higher CPN uptake however these cells were the most resistant to CPN-PDT cytotoxicity compared to MO59K and U-87 MG GBM cells. This could indicate that the antioxidant enzyme is critical for the heterogeneity in GBM [26]. NP acts in two ways once it has been delivered to the intended location in the brain. One that results in lymphocyte aggregation, which enables T-cells to destroy cancer cells. The other by which cancer cells get deactivated when PS NPs aggregate at the target site where the light source excites them and degenerates the cytoplasmic organelles [27].

Nanoscintillators such as LaF3:Tb convert X-rays into visible light to activate PS via Fluorescence resonance energy transfer (FRET), enabling enhanced PDT [28]. Chen et al., 2017 demonstrated non-invasive PDT in 9 L glioma cells using meso‑tetra(4-carboxyphenyl) porphyrin (MTCP) -loaded scintillating NPs and soft X-rays. IR-780 was stabilized in liposomes, improving apoptosis and ROS generation. Convection-enhanced delivery (CED) was used to overcome the BBB, enhancing tumor selectivity via localized pressure-driven flow (Fig. 1A) [29]. The effectiveness of NP-based PDT for GBM depends on NP type, modifications, light wavelength, and tumor destruction mechanisms, summarized in Table 1.

Table 1.

Nano-PDT therapeutic approaches for different cancer types, nanoparticle/modifications, wavelength of PDT light used and their mechanism of tumor destruction/treatment.

Type of Cancer	Nanoparticle/Modification	Wavelength of Light Used	Mechanism of Tumor Destruction/Treatment	Reference
Glioblastoma (GBM)	AGuIX functionalized with KDKPPR peptide	NIR-652 nm	Targets NRP-1 receptor, activates M1 macrophages (proinflammatory, antitumor) while inhibiting M2 phenotype	[16]
	Upconversion NP (UCNP) (lanthanum-doped, mesoporous silica-coated, Gd-doped UCNPs)	IR-780 nm	Enhances light penetration, enables imaging, allows ROS generation for tumor destruction	[14]
	AGuIX-TPP (polysiloxane-based nanoplatform with meso tetraphenylporphyrin)	NIR-630 nm	Targets NRP-1 receptor, enables ROS production, enhances tumor retention	[24]
	Gold Nanoparticles (AuNPs) conjugated with EGF peptide (EGFpep-AuNP) loaded with Pc4(second-generation photosensitizer)	NIR-675nm	Targets EGFR, enhances drug delivery, increases lysosomal uptake, improves biodistribution	[17]
	Dual-targeted AuNP (EGFpep+ Tfpep)-AuNPs loaded with Pc 4	NIR-665nm	Dual-targeting of EGFR and transferrin receptors, increased drug uptake and apoptosis	[6]
	Terbium (Tb)-doped LaF3 nanoscintillators	X-ray (50 kVp)	Converts X-ray into light, excites PS via FRET, generates singlet oxygen	[30]
	Scintillating nanoparticles with meso‑tetra(4-carboxyphenyl) porphyrin (MTCP)	X-ray (180 kVp)	ROS generation, selective cytotoxicity in glioma cells	[28]
	Liposomal formulation of PS	IR-780nm	Maintains photostability, enhances ROS production and apoptosis, improves BBB penetration using CED	[29]
	Metalated porphyrin-doped conjugated polymer nanoparticles (CPN)	NIR-670nm	Induces ROS generation, alters tumor microenvironment, heterogeneous response in GBM cells	[26]
	Cholesteryl bovine serum albumin NP loaded with triphenyl phosphonium-pheophorbide a (TPP-PheoA)	NIR-670nm	Targets mitochondria via folate receptors, enhances tumor accumulation, induces apoptosis	[8]
	Neutrophils (NE) loaded with Hexagonal boron nitride NPs BNPD-Ce6	NIR-808nm	Enhances ROS generation and cytotoxicity for anti-GBM PDT	[23]
Breast Cancer	Biomimetic nanoformulation of prodrug CM-SSZ-SS-PS	IR-660nm	Inhibition of ROS resistance via SLC7A11 inhibition, enhanced PDT effect	[46]
	Gold nanoparticles (AuNP) loaded with Hypericin (Hyp)	Visible light-594 nm	Increased cellular uptake of PS, enhanced PDT efficiency	[35]
	Silica nanoparticles (SiNPs) loaded with Safranin (SF)	IR-650nm	Improved ROS generation, reduced exposure time, safer than standalone SF	[7]
	Zwitterionic polymer lipid-liposomal nanoformulation encapsulating methylene blue (MB)	IR-668 nm	Enhanced ROS generation, fast intracellular uptake, apoptosis induction	[9]
	Cancer cell membrane (CM)-cloaked multifunctional UCNPs with PEG-TK-DOX and rose bengal (RB)	NIR-980nm	Dual chemo-PDT effect with ROS-triggered release of DOX	[43]
	Redox-responsive docetaxel/HA-cys-DHA/Ce6 (DTX/CHD) NP	IR-660nm	PDT with chemotherapy, enhanced tumor site accumulation, ROS production	[40]
	Chondroitin sulfate-based NP with quercetin, chlorin e6 (Ce6), and paclitaxel	IR-660nm	ROS generation, MDR overcoming, lung metastasis reduction	[41]
	PPCNPs-Ce6/FA	IR-660nm	ROS production, reduced P-gp expression, tumor selectivity	[42]
	Gold nanoparticles (AuNPs) conjugated with zinc-phthalocyanine derivative, C11Pc and PEG	IR-633nm	Targeted PDT via HER2 receptor, singlet oxygen production	[33]
	AuNP combined with cannabidiol (CBD)	Not specified	Targets CB2-R in cancer cells, prevents tumor progression and metastasis	[34]
	Lactose-functionalized AuNPs loaded with zinc-phthalocyanine PS (C3Pc and C11Pc)	NIR-680nm	Targeting via galectin-1 receptor, enhanced PDT effect	[31]
	5, 10, 15-Tris (4-nitrophenyl)-20-hydroxylphenylporphyrin complex metalated with gallium chloride conjugated to biotin combined with bimetallic nanoparticles (B-Au-Ag).	LED-625nm	Increased quantum yield of singlet oxygen and increased cellular uptake.	[37]
	AgNPs modified with liposomes (Lip) loaded with PS zinc pthalocyanine tetrasulfonate (Lip@ZnPcS4) and synthesized NPs such as AgNPs, AgNPs-Lip, Lip@ZnPcS4	IR-660nm	Improved ROS generation and cytotoxicity	[38]
	Multifunctional silk-based nanoparticles (SFNPs) encapsulating Epirubicin (EPI), copper sulfide (CuS), oxygen-independent alkyl radical generator AIPH, coated with polydopamine (PDA) and functionalized with surface-bound folic acid (FA).	NIR-808nm	Enhanced intracellular drug accumulation and cellular uptake and low toxicity toward non-cancerous cells.	[39]
Lung Cancer	PLGA-lipid hybrid NP loaded with pTHPP	IR-652nm	Overcomes MDR, enhances ROS generation, apoptosis induction	[47]
	Gold nanoprisms (GNPs)@PEG/Ce6-PD-L1 peptide.	IR-660nm	Combined PDT & PTT, PD-L1 targeting, enhanced tumor accumulation	[48]
	Gefitinib PLGA NP with 5-ALA	IR-630nm	Combined chemo-PDT (CPDT), anti-angiogenesis, anti-inflammatory effects, apoptosis	[49]
	TiOx nanocomposites (YSA-PEG-TiOX) with Cantharidin (CTD)	X-ray	ROS generation, targeted therapy using EphA2-overexpressing A549 cells	[50]
	Iridium-coordinated (IPC) nanodrugs (Ce6, Iridium, PVP)	IR-630nm	PDT enhancement by reducing hypoxia, GSH depletion, and immune modulation	[51]
	Hydroxyapatite zirconium nanoparticles (HApZr)	Xray-5 Gy	TNF-α-induced ROS generation, cytotoxicity to lung cancer cells	[57]
	ICG-encapsulated erlotinib-modified chitosan NP (ICG-ERL-CS NPs)	NIR-800nm	Synergistic CPDT, increased ROS, improved apoptosis	[53]
	UCNPs with SOD1 gene silencing	NIR-980nm	Converts NIR to visible light, enhances ROS generation, gene silencing for MDR reduction	[55]
	Folate-functionalized NPs loaded with PS	IR-670nm	FOLR1 targeting, enhanced ROS generation, reduced damage to healthy tissue	[56]
	Photoactive curcumin–silver nanoparticle–polymer conjugate (Cum–PEG–BpAgNPs)	Visible light-470nm	Promotes enhanced ROS generation and apoptosis	[54]
Prostate Cancer	RB-encapsulated chitosan NPs	Visible light −532nm	Increased bioaccumulation, enhanced ROS generation, apoptosis	[61]
	CoFe₂O₄-HPs-FAs (magnetic NPs conjugated with hematoporphyrin and folic acid)	IR-635nm	ROS generation, targeted tumor cell destruction	[58]
	Cu-doped Bi₂S₃ nanorods	NIR	Cu enhances electron-hole separation, increased ROS, apoptosis via cell cycle inhibition	[59]
	HSA-ICG-Ce6 NPs	NIR- 808nm	Ce6 PDT activation, ICG-mediated PTT, oxygen recovery for enhanced therapy	[5]
	HSA@IR780@DTX	NIR	Combined PDT-PTT with chemotherapy, enhanced ROS generation, tumor necrosis	[62]
	Porphyrin-grafted lipid microbubbles (PLMs)	IR-635nm	Ultrasound-controlled accumulation, enhanced tumor penetration, ROS-mediated apoptosis	[65]
	Multilayer capsules with Selenium (Se) NPs and Au nanorods	NIR 750- 1400 nm	PDT-PTT synergy, heat generation, IR induction, potential for antibody therapy	[63]
	PSMA-targeted magnetic NPs (MNPs)	NIR-690nm	PDT-induced tumor vasculature disruption, enhanced NP penetration, improved MRI contrast	[64]
Pancreatic cancer	midkine nanobody (Nbs)-PCPDTTBTT polymeric NPs	NIR-690nm	Targeting tumor microenvironment (TME), ROS generation, immunogenic cell death (ICD), antitumor immunity activation	[66]
	Re(I) bisquinolinyl metal complex-LCNPs	Visible light-450nm	PDT-chemotherapy synergy, enhanced cellular uptake, increased tumor inhibition with gemcitabine	[71]
	P@-Gem-HSA-NPs	IR-660nm	Optical fluorescence for drug tracking and imaging, singlet oxygen generation, improved drug release and tumor inhibition	[67]
	UCNP@PMVEMA-THPC nanoconjugates	NIR-980nm	Surface modification for stability, ROS generation, enhanced cellular uptake, significant cancer cell death	[68]
	Theranostic nanocells	NIR-800nm	Real-time tumor imaging, PDT activation, anti-VEGF therapy for tumor suppression	[69]
	Eutectic gallium indium NPs (EGaPs) conjugated with HA and BPD	NIR-690nm	EGaPs as ROS generators, intracellular tumor cell destruction, tumor size reduction	[70]
Melanoma	Colloidal transdermal bilosomes with MB (PS) and curcumin	IR-670nm	Improved targeting selectivity, increased biocompatibility, cytotoxicity, and reduced cell viability via PDT	[72]
Oral Squamous Cell Carcinoma	5-ALA incorporated AuNPs	IR-635nm	Suppression of cancer cell proliferation, enhanced ROS production, and increased cytotoxicity in tumor cells	[73]
Rectal Cancer	Zwitterionic near-infrared cyclodextrin derivative complexed with pheophorbide-conjugated ferrocene	660nm-IR, 880nm-NIR	Tumor penetration via transcytosis, enhanced specificity, photobleaching property, dual therapy of CPDT	[74]

Breast cancer

Triple-negative breast cancer (TNBC) remains a leading cause of death in women due to lack of human epidermal growth factor receptor-2 (HER-2), resistance to traditional therapies, and high metastasis rates [32]. Gold NPs (AuNPs) have been explored in PDT applications for TNBC. Stuchinskaya et al., 2011, conjugated AuNPs with a zinc-phthalocyanine derivative (C11Pc), PEG, and anti-HER2 antibodies, selectively targeting HER2-overexpressing cells while generating singlet oxygen for PDT [32]. AuNPs have also been combined with cannabidiol (CBD), a Cannabis sativa compound with anti-cancer properties. CBD activates cannabinoid receptors CB1-R and CB2-R, with CB2-R highly expressed in breast cancer. Binding to CB2-R induces apoptosis and inhibits tumor progression. This PDT-CBD strategy has potential to improve patient outcomes by reducing toxicity and improving quality of life, although further investigation is needed [[33], [34], [35]].

In another study, hypericin (Hyp), a hydrophobic PS, was adsorbed onto carboxylic acid-functionalized AuNPs using PEG3000. This conjugation retained Hyp’s photochemical activity, improved cellular uptake, and showed enhanced PDT effects in MCF-7 cells (Fig. 2D) [36]. Similarly, metallized porphyrin, 5,10,15-Tris (4-nitrophenyl)-20-hydroxylphenylporphyrin complexes conjugated with biotin and Au-Ag bimetallic NPs improved singlet oxygen quantum yield and demonstrated low dark toxicity, highlighting their potential as effective PSs (Fig. 2C) [37].

Fig. 2.

A. Schematic representation of AgNPs@Lip@ZnPc nanoparticles for PDT, showing cellular uptake, ROS generation, and apoptosis induction under laser irradiation [38]. B. Scheme of the experiment [9]. C. The cell morphology for control (before) and after PDT treatment using 2-B-Au-Ag [37]. D. Morphology at 12 h post Hyp-AuNP compound PDT treatment [35]. E. TEM visualization and analysis of SF encapsulated by SiNPs [7].

Green-synthesized AgNPs were modified with liposomes and loaded with zinc phthalocyanine tetrasulfonate (Lip@ZnPcS4). These nanocomplexes exhibited enhanced cytotoxicity and apoptotic potential against MCF-7 cells (Fig. 2A) [38]. Silica nanoparticles (SiNPs) were also used as carriers for Safranin (SF), offering improved delivery, lower toxicity, and efficient ROS generation. Encapsulated SF reduced required exposure time from 50 to 28 min, improving PDT performance (Fig. 2E) [7].

A microfluidics-assisted strategy to develop multifunctional silk fibroin-based nanoparticles (SFNPs) were engineered using Epirubicin (EPI), copper sulfide (CuS), and AIPH (a heat-activated radical generator), then coated with polydopamine (PDA) and folic acid (FA). Under 808 nm NIR light, these CuS-EPI-AIPH@SF-PDA-FA NPs released radicals and EPI, achieving significant cancer cell killing with minimal harm to healthy cells [39]. Lactose-functionalized AuNPs targeting galectin-1 receptors on MDA-MB-231 cells were studied with zinc phthalocyanine PSs C3Pc and C11Pc. While only lactose-C3Pc-AuNP induced significant cytotoxicity under PDT, the study highlights carbohydrate-functionalized NPs for targeted therapy [31].

A redox-responsive nanoformulation using docetaxel/HA-cys-DHA/Ce6 (DTX/CHD) demonstrated successful delivery to CD44-overexpressing MCF-7 cells. Chlorin e6 (Ce6) generated ROS for PDT, while docosahexaenoic acid (DHA) and hyaluronic acid (HA) served as safe, biocompatible carriers [40]. Another chondroitin sulfate-based NP loaded with quercetin, paclitaxel, and Ce6 effectively induced ROS, overcame multidrug resistance (MDR), and inhibited metastasis to the lung [41]. To further combat MDR, polyethylenimine−PEGylated ceria nanoparticles (PPCNPs) loaded with Ce6 and folic acid (PPCNPs-Ce6/FA) were designed. Upon NIR exposure, these NPs induced lysosomal membrane permeabilization (LMP), reduced P-glycolprotein (P-gp) expression, and showed strong phototoxicity even at low doses, along with prolonged circulation and tumor selectivity [42].

Cancer cell membrane-cloaked UCNPs were developed with ROS-sensitive polyethylene glycol-thioketal-doxorubicin PEG-TK-DOX and rose bengal (RB). These CM@UCNP-RB/PTD NPs enabled immune activation and chemo-PDT. CD73 blockade improved the immunogenic response [43]. Resistance to ROS remains a major challenge in PDT, often requiring higher PS concentrations and risking MDR [44]. Inhibiting solute carrier family 7 member 11 (SLC7A11), which regulates ROS via antioxidant enzyme glutathione peroxidase 4 (GPX4), enhances PDT efficacy. Li et al., 2024 developed a biomimetic nanoformulation of prodrug CM-SSZ-SS-PS which consisted of the PS which is a cyanine derivate, disulfide bond (-SS-), SLC7A11 inhibitor (SSZ) and decorated with a cancer cell-macrophage hybrid membrane 4T1 and RAW 264.7. The PS and SSZ upon exposure to high GSH levels in TNBC cells, enhances the therapeutic outcomes [45,46]. Methylene blue (MB), although a potent PS, has low cellular uptake. A zwitterionic polymer lipid (poly(12-(methacryloyloxy)dodecyl phosphorylcholine) was made into liposomal nanoformulation as a drug carrier and MB was encapsulated in it. It improved MB's ROS generation and apoptotic effect (Fig. 2B). These liposomes offered better protection, prolonged circulation, and superior cellular uptake over free MB [9]. The efficacy of NP-based PDT for breast cancer can be assessed based on the type of NP and its modifications, the wavelength of light used, and the mechanism of tumor destruction/treatment, as outlined in Table 1.

Lung cancer

Lung cancer is a leading global cause of cancer-related deaths. PDT is particularly promising for early-stage lung cancer treatment. Drug resistance, such as P-gp overexpression in A549RT-eto cells, complicates therapy. To address this, 5,10,15,20-Tetrakis(4‑hydroxy-phenyl)-21H,23H-porphine (pTHPP) was encapsulated in PLGA-lipid hybrid NPs, enhancing intracellular drug accumulation, ROS generation, and apoptosis in resistant cells [47]. Gold nanoprisms (GNPs) modified with PD-L1 peptides (GNPs@PEG/Ce6-P) enabled targeted PDT and PTT in HCC827 lung cancer cells, which overexpress programmed death ligand 1 (PD-L1). GNPs@PEG/Ce6-PD-L1 peptide (GNPs@PEG/Ce6-P) acts a nanoprobe for PDT because of the targeting effect of PD-L1 which is overexpressed in cancer cells. Ce6 served as the PS, and PEG coating improved biocompatibility. Imaging confirmed enhanced intratumoral accumulation and biodistribution from the synergistic effect of PTT and PDT [48].

Zhang et al., 2020 combined 5-aminolevulinic acid (5-ALA) with gefitinib-loaded PLGA NPs (GNPs) for pulmonary delivery on adenocarcinomic human alveolar basal epithelial cells (A549). This chemo-photodynamic therapy (CPDT) approach showed enhanced anti-cancer, anti-inflammatory, and anti-angiogenic effects in A549 cells compared to monotherapies [49]. TiOx nanocomposites (YSA-PEG-TiOx) loaded with cantharidin (CTD) were developed for CPDT in non-small cell lung cancer (NSCLC). Targeting peptide YSA improved uptake in EphA2-overexpressing A549 cells. TiOx served both as a nanocarrier and ROS generator under X-ray irradiation, enhancing cytotoxicity and selective tumor targeting (Fig. 3C) [50]. Li et al., 2025 created iridium-coordinated nanodrugs (IPC) using Ce6, iridium ions, and polyvinylpyrrolidone (PVP). These self-assembled nanodrugs accumulate in tumors, degrade in acidic environments, and mimic catalase to reduce hypoxia and glutathione, thereby enhancing PDT-induced immunogenic cell death [51].

Fig. 3.

A. Using liposomal berberine nanoparticles (Lipo@BBR) in PDT of A459 lung cancer spheroid cells [56]. B. Proposed structures of Cum–PEG–BpAgNPs: reaction (1) involves the sonication of Ag (BpAgNPs) in PEG, followed by 24 h incubation at room temperature in the dark; in reaction (2), curcumin was sonicated in PEG thiolated silver (PEG–BpAgNPs), followed by incubation in the dark at 4 °C for 24 h. A and B represent the possible structures of curcumin–silver nanoparticle–polymer conjugate (Cum–PEG–BpAgNPs) formed [54]. C. (a) Schematic illustration of the preparation of YSA-PEG-TiOx/CTD. (b) Schematic illustration of YSA-PEG-TiOx/CTD for EphA2 targeting drug delivery and the photodynamic effect upon X-ray irradiation [50]. D. (A) Images and the size (μm) of A549 spheroid before and post-PDT in various sessions, (scale bars: 200 μm) [56].

Additionally, by reducing hypoxia, these nanodrugs help prevent cancer metastasis by improving the immune response, lowering PD-L1 expression, and increasing the number of immune cells that attack cancer cells. Hydroxyapatite zirconium (HApZr) NPs increased ROS generation via TNF-α-induced pathways and showed higher uptake in lung cancer tissues than in normal lung, promoting apoptosis [52]. Zhang et al., 2019 developed indocyanine green (ICG)-encapsulated erlotinib-modified chitosan NP (ICG-ERL-CS NPs) for NIR-triggered PDT. This system enhanced solubility, bioavailability, and ROS production in lung cancer cells, showing superior cytotoxicity and apoptosis compared to free erlotinib or ICG alone [53]. Kah et al., 2025 created a curcumin-based photoactive system (Cum–PEG–BpAgNPs) for 470 nm PDT, effectively targeting lung cancer cells and cancer stem cells. This formulation induced significant ROS-mediated cytotoxicity (Fig. 3B) [54]. To overcome MDR in NCI-H23 lung cancer, UCNPs were used for dual-action PDT and SOD1 gene silencing. UCNPs converted NIR to visible light to activate the PS, while siRNA knocked down drug-resistance genes. The system improved apoptosis and reduced resistance in vitro and in vivo [55]. PDT using NP designed to exploit the overexpression of folate receptor 1 (FOLR1) on cancer cells is another approach which has been tried by Kato et al., 2017. Folate-functionalized NPs loaded with a PS selectively bind to FOLR1-expressing tumor cells, enhancing cellular uptake and PDT efficiency. The NPs produced ROS when activated by light, which enhanced apoptosis while reducing harm to healthy tissues. Folate receptor targeting enhanced tumor suppression and reduced side effects compared to non-targeted PDT [56]. Berberine (BBR), a natural PS, showed poor solubility, which was overcome by liposomal encapsulation (Lipo@BBR). These PEGylated liposomes improved BBR uptake and efficacy in A549 lung cancer cells, suggesting a promising delivery system (Fig. 3A, 3D) [56]. The efficacy of nanoparticle-based PDT for lung cancer can be assessed based on the type of nanoparticle and its modifications, the wavelength of light used, and the mechanism of tumor destruction/treatment, as outlined in Table 1.

Prostate cancer

In men prostate cancer (PCa) is one major causes of death globally. To enhance treatment efficacy, various NP-based PDT strategies have been explored. In an in vitro study conducted by Choi et al., 2017, multifunctional magnetic NPs CoFe₂O_4—HPs-FAs conjugated with hematoporphyrin (HP) were synthesized which included folic acid (FA) as shown in Fig. 4A. The PC3 cells were exposed to LED light and ROS was generated which effectively killed the cancer cells as shown in Fig. 4C [58].

Fig. 4.

A. Fabrication procedure for the multifunctional magnetic nanoparticles [58]. B. A schematic illustration to show the formation of HSA@IR780@DTX nanoparticles by self-assembly between HSA, DTX, and IR780 [62]. C. The synthesis process of Cu-Bi₂S₃ nanorods and their mechanism of action in PDT for PCa their role in enhancing efficacy by increasing the production of reactive oxygen species [59]. D. Schematic of the microbubble-based, ultrasound-assisted PDT strategy. (a) Preparation of PGL-MB and its transformation from microbubbles to nanoparticles under exposure to low-frequency ultrasound (LFUS). (b) Experimental process of in vivo PDT under the guidance of contrast enhances ultrasound (CEUS) imaging, followed by ultrasound targeted microbubble destruction (UTMD) [65]. E. NIR imaging and biodistribution analysis. The fluorescence images of mice with PCa injected with NPs (the white arrows indicated tumor area) [62].

Copper (Cu)-doped Bi₂S₃ nanorods were also investigated for PCa therapy. Doping reduced electron-hole recombination, enhancing O₂ adsorption and activation. Under light exposure, Cu-Bi₂S₃ efficiently produced ROS and inhibited PC3 cell proliferation via apoptosis [59].

Xanthene fluorescent dye functions as a PS through type II PDT mechanisms [60]. However, limited membrane permeability reduces its efficiency. Encapsulation into chitosan NPs enhanced RB uptake and ROS production in PC3 cells, showing greater cytotoxicity compared to normal MCF10A cells [61]. Ce6 and ICG-loaded human serum albumin (HSA-ICG-Ce6 NPs) were developed to combine PDT and PTT. ICG served as both a quencher and PTT agent under NIR irradiation (808 nm), while Ce6 generated ROS. The system showed tumor-specific activation and high phototherapeutic efficiency [5]. Another strategy that uses HSA NP is to load DTX which is the first choice for chemotherapeutic treatment of PCa, with the dye IR780 iodide. HSA@IR780@DTX mainly was developed for combination therapy of PDT and PTT for targeted imaging and combination of PDT-PTT with chemotherapy (Fig. 4B and 4E). HSA binds to both DTX and IR780 and induces self-assembly of HSA. Enhanced ROS generation and cellular uptake was also observed with severe tumor necrosis at the laser site alongside growth inhibition [62].

A hybrid carrier with multilayer capsules incorporated with selenium (Se) NPs and Au nanorods aids in the production of ROS for PDT-PTT treatment strategy. These NPs absorbed NIR light to generate localized heat and ROS, leading to cytotoxic effects in PC3 cells. This system also holds potential for combination with antibody therapy [63].

Targeted delivery of magnetic nanoparticles (MNPs) to Prostate-specific membrane antigen (PSMA) -expressing prostate tumors using PSMA-targeted PDT was developed. PDT-induced vascular permeability enhancement facilitated increased accumulation of magnetic NPs, improving MRI contrast and allowing combination with hyperthermia or drug delivery. PSMA-targeted PDT induced selective tumor damage while sparing normal tissues [64].

Porphyrin-grafted lipid microbubbles (PLMs) were another innovation for ultrasound-triggered PDT in PCa. Upon intravenous administration, microbubbles were selectively accumulated in prostate tumors and activated via focused ultrasound. Light exposure activated the porphyrin PS, inducing ROS production and cancer cell apoptosis. In vivo, PLMs significantly reduced tumor size with minimal toxicity (Fig. 4D) [65]. The efficacy of nanoparticle-based PDT for PCa can be assessed based on the type of nanoparticle and its modifications, the wavelength of light used, and the mechanism of tumor destruction/treatment, as outlined in Table 1.

Pancreatic cancer

One particularly aggressive type of pancreatic cancer is called pancreatic ductal adenocarcinoma (PDAC) with a survival rate of less than 10 %, primarily due to its resistance to therapies such as chemotherapy and its immunosuppressive tumor microenvironment (TME). Using tumor-specific midkine (MDK) nanobodies (Nbs), which effectively carry semiconducting polymeric NPs (poly[2,6-(4,4-bis(2-ethylhexyl)-4H-cyclopenta-[2,1-b:3,4-b]dithiophene-alt-4,7-bis(thiophen-2-yl)benzo-2,1,3-thiadiazole], PCPDTTBTT) to the tumor site, a light-responsive platform was created to target the TME of PDAC. These NPs locally generate ROS, inducing apoptosis. Given that immunogenic cell death (ICD) is recognized as an effective therapeutic approach, PDT was employed to trigger immunogenic cell death and stimulate a systemic immune response against tumor cells. Through precise local PDT, the combination of Nbs with photodynamic NPs improves antitumor immunity and efficiently inhibits tumor growth, increasing the effectiveness of immunotherapy for PDAC [66]. Pancreatic cancers metastasise by lymph node metastasis which is a characteristic of these cancers. Pyropheophorbide-a (P@)-Gem-human serum albumin (HSA)-NPs were developed where albumin acts as nanocarrier for gemacitabine (Gem), modified by P@ as PS explored on pancreatic cell line BxPC-3-LN7. Under NIR irradiation, P@ produces optical fluorescence which is useful for tracking the drug delivery and also for imaging. P@-Gem-HSA-NPs could effectively produce singlet oxygen under light exposure and showed, tumor inhibition higher drug release rates, good encapsulation efficiency and controlled release mainly due to interaction between P@ and surface of NPs (Fig. 5A) [67].

Fig. 5.

A. A schematic illustration showing the composition of this triple-functional NP [67] B. Schematic representation of the synthetic procedures of THPC-conjugated UCNP@PMVEMA particles and 980 nm NIR-induced PDT of pancreatic adenocarcinoma in an animal model [68]. C. Combinatory effects of gemcitabine with Re(I) bisquinolinyl complex in pancreatic cancer cells (HSA model) [71]. D. Percentage of cells undergoing apoptosis was determined using annexin V/7-AAD flow cytometric analysis of SW1990 pancreatic cancer cells treated with IC₅₀ values of Gem:Re LCNPs (1:1) and blank LCNPs for 48 h. Bars indicate the mean ± standard deviation of three independent experiments. Asterisks (*) represent statistical significance in comparison with control cells and cells treated with blank LCNPs (p < 0.05, Student’s t-test) [71]. E. Schematic depiction of the protocol to fabricate stable EGaPs [70].

UCNPs were surface modified using poly(methyl vinyl ether-alt-maleic acid) (PMVEMA) and temoporfin (THPC) PS in a study by Shapoval et al., 2023, to ensure stability of particles. In order to achieve direct excitation of THPC, co-doping of Fe²⁺, Yb³⁺, and Er³⁺ ions in the NaYF4 host caused upconversion emission and luminescence intensity of particles in the red region. UCNP@PMVEMA-THPC nanoconjugates in vitro studies using pancreatic adenocarcinoma cells demonstrated effective cellular uptake, ROS generation, and significant cancer cell death upon NIR irradiation along with promising efficacy in treatment of pancreatic cancer (Fig. 5B) [68]. Additionally, Spring et al., 2010 created theranostic nanocells for the simultaneous imaging and PDT of pancreatic cancer. Multifunctional nanocells integrate both diagnostic and therapeutic functions, for real-time tumor imaging alongside effective treatment with combination of anti-VEGF therapy. These nanocells incorporate PS for PDT activation and anti-VEGF agent Avastin into the tumor cells. Nanocells efficiently accumulated in tumor tissues due to their optimized size and surface properties, ensuring enhanced EPR effects [69]. Eutectic gallium indium NP (EGaIn) was conjugated with HA as targeting ligand and benzoporphyrin (BPD) derivative as PS forming EGaPs. A homogenous mixture with a melting point lower than the constituents' is called a eutectic mixture. EGaPs act as promising carriers and can generate ROS intracellularly to damage the cancer cells and tumor size reduction upon NIR irradiation [70]. Similarly, Re(I) bisquinolinyl metal complex is used as a PS alongside gemcitabine incorporated into liquid crystalline NP (LCNPs) against PDAC (Fig. 5E). This complex exhibited synergistic action with gemcitabine, enhancing cellular uptake and therapeutic efficacy. Re(I) bisquinolinyl complex in combination with gemcitabine showed greater tumor inhibition in BxPC3 cell line than when used alone. This strategy can also be combined with chemotherapy of gemcitabine for improved efficacy and dose reduction (Fig. 5C and 5D) [71]. The efficacy of nanoparticle-based PDT for pancreatic cancer can be assessed based on the type of nanoparticle and its modifications, the wavelength of light used, and the mechanism of tumor destruction/treatment, as outlined in Table 1.

Miscellaneous

Nano-PDT being a non-invasive technique is preferred for various kinds of cancers. One of the most aggressive types of skin cancer is melanoma. Since it is mostly resistant to conventional treatment of cancers, an approach with better targeting selectivity and biocompatibility is required. l-α-phosphatidylcholine, sodium cholate, Pluronic® P123, and cholesterol were co-stabilized with self-assembled bilosomes to create a unique colloidal transdermal nanoplatform. The hybrid cargo complex incorporated methylene blue as a photosensitizer and curcumin as a polyphenolic agent within the bilosome's lipid layer. Human epithelial skin melanoma A375 cells were treated with this nanoplatform which confirmed cytotoxicity and PDT also reduced the cell viability [72]. When using PS for melanoma PDT, one factor to consider is the presence of melanin because it possesses antioxidant qualities and absorbs visible light similar to most PS, which reduces the ROS produced during PDT. Therefore, nanocarriers can be used which can incorporate the PS to increase specificity, optical absorption and to increase the solubility to make PDT more efficient [72]. Similarly, oral squamous cell carcinoma is another common type of cancer which that poses a challenge to the global health and is the 6th most common type of cancer. PDT is extensively used in managing superficial skin cancers because of its improved cosmetic results, minimal invasiveness etc. 5-ALA can be incorporated into AuNPs to supress the proliferation of oral cancer cells and enhances the ROS production as well as cytotoxicity in tumor cells [73]. Nguyen et al., 2024 synthesized a zwitterionic near-infrared cyclodextrin derivative of heptamethine cyanine complexed with pheophorbide-conjugated ferrocene to produce nanotherapeutics which could eradicate orthotopic rectal tumors by enhancing the specificity and photobleaching properties. NPs were penetrated into the tumors via transcytosis and dual therapy of CPDT could be utilized [74]. The efficacy of nanoparticle-based PDT for skin cancer, oral cancer and rectal cancer can be assessed based on the type of NP and its modifications, the wavelength of light used, and the mechanism of tumor destruction/treatment, as outlined in Table 1

Conclusion

PDT is a promising alternative due to its targeted approach in inducing cell death while minimizing damage to surrounding healthy tissues. However, despite its advantages, traditional PDT faces several limitations, such as poor tissue penetration of light, oxygen dependence, and non-specific accumulation of PS, which hinder its widespread clinical adoption. The integration of nanotechnology into PDT has significantly improved its efficacy by addressing these challenges. NPs serve as effective PS carriers, enhancing their solubility, stability, and tumor selectivity while reducing systemic toxicity. Moreover, nanomaterials such as dendrimers, liposomes, polymeric NPs, gold NPs, etc. have been extensively explored for their potential for improving PDT outcomes. Nanocarriers further enhance PDT by enabling co-delivery of chemotherapeutic agents, facilitating multimodal cancer treatment approaches. The EPR effect and functionalization of NPs with tumor-targeting ligands improve selective PS accumulation in cancerous tissues, minimizing off-target effects and reducing toxicity. Additionally, different types of cancer that can be effectively treated with nano-PDT has been explored in this paper. However, continuous research and technological advancements hold great promise in making PDT a safer, more effective, and accessible cancer treatment option. The future of PDT depends on advancing more efficient, biocompatible, and multifunctional nanomaterials to improve treatment outcomes while reducing adverse effects. By overcoming current limitations, nanotechnology-based PDT has the potential to revolutionize cancer therapy, providing a more precise, efficient, and safer approach to cancer treatment.

Future perspectives

Despite significant progress in integrating nanotechnology with PDT for cancer treatment, several challenges persist that present opportunities for future research. A major gap lies in the limited tumor-specific accumulation and controlled drug release of current nano-based photosensitizer delivery systems. Future efforts should focus on the development of smart, stimuli-responsive nanocarriers that can selectively activate PDT within the tumor microenvironment, minimizing sdamage to healthy tissues. Additionally, overcoming tumor hypoxia, which limits PDT efficacy through oxygen-generating or oxygen-carrying nanomaterials remains a critical area for advancement. Long-term biosafety, pharmacokinetics, and clinical translatability of these nano-formulations are still underexplored, underscoring the need for comprehensive in vivo studies and standardized regulatory pathways. Moreover, integrating nanotechnology-enabled PDT with immunotherapy or gene therapy could provide synergistic and durable anti-cancer effects.

Declaration of generative AI and AI-assisted technologies in the writing process

During the preparation of this work, the author(s) used Quillbot to paraphrase. After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication.

Data availability

No data was used for the research described in the article.

CRediT authorship contribution statement

Nanda Rajagopal: Writing – review & editing, Writing – original draft. Ipshita Das: Writing – review & editing, Conceptualization. Annanya Kapur: Writing – review & editing. Shruthi Nayak: Writing – review & editing. Yashaswini Reddy: Writing – review & editing. Babitha Kampa Sundara: Validation, Supervision, Funding acquisition, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.